“Virology, transmission, and pathogenesis of SARS-CoV-2 - The BMJ” plus 3 more
“Virology, transmission, and pathogenesis of SARS-CoV-2 - The BMJ” plus 3 more |
- Virology, transmission, and pathogenesis of SARS-CoV-2 - The BMJ
- Mechanisms of COVID‐19‐induced cardiovascular disease: Is sepsis or exosome the missing link? - Wiley
- Vitamin C and COVID-19: A Review - News-Medical.Net
- Single-cell analysis identified lung progenitor cells in COVID-19 patients - DocWire News
| Virology, transmission, and pathogenesis of SARS-CoV-2 - The BMJ Posted: 23 Oct 2020 02:28 AM PDT
What you need to know
Since the emergence of SARS-CoV-2 in December 2019, there has been an unparalleled global effort to characterise the virus and the clinical course of disease. Coronavirus disease 2019 (covid-19), caused by SARS-CoV-2, follows a biphasic pattern of illness that likely results from the combination of an early viral response phase and an inflammatory second phase. Most clinical presentations are mild, and the typical pattern of covid-19 more resembles an influenza-like illness—which includes fever, cough, malaise, myalgia, headache, and taste and smell disturbance—rather than severe pneumonia (although emerging evidence about long term consequences is yet to be understood in detail).1 In this review, we provide a broad update on the emerging understanding of SARS-CoV-2 pathophysiology, including virology, transmission dynamics, and the immune response to the virus. Any of the mechanisms and assumptions discussed in the article and in our understanding of covid-19 may be revised as further evidence emerges. What we know about the virusSARS-CoV-2 is an enveloped β-coronavirus, with a genetic sequence very similar to SARS-CoV-1 (80%) and bat coronavirus RaTG13 (96.2%).2 The viral envelope is coated by spike (S) glycoprotein, envelope (E), and membrane (M) proteins (fig 1). Host cell binding and entry are mediated by the S protein. The first step in infection is virus binding to a host cell through its target receptor. The S1 sub-unit of the S protein contains the receptor binding domain that binds to the peptidase domain of angiotensin-converting enzyme 2 (ACE 2). In SARS-CoV-2 the S2 sub-unit is highly preserved and is considered a potential antiviral target. The virus structure and replication cycle are described in figure 1.  Fig 1 (1) The virus binds to ACE 2 as the host target cell receptor in synergy with the host's transmembrane serine protease 2 (cell surface protein), which is principally expressed in the airway epithelial cells and vascular endothelial cells. This leads to membrane fusion and releases the viral genome into the host cytoplasm (2). Stages (3-7) show the remaining steps of viral replication, leading to viral assembly, maturation, and virus release Coronaviruses have the capacity for proofreading during replication, and therefore mutation rates are lower than in other RNA viruses. As SARS-CoV-2 has spread globally it has, like other viruses, accumulated some mutations in the viral genome, which contains geographic signatures. Researchers have examined these mutations to study virus characterisation and understand epidemiology and transmission patterns. In general, the mutations have not been attributed to phenotypic changes affecting viral transmissibility or pathogenicity. The G614 variant in the S protein has been postulated to increase infectivity and transmissibility of the virus.3 Higher viral loads were reported in clinical samples with virus containing G614 than previously circulating variant D614, although no association was made with severity of illness as measured by hospitalisation outcomes.3 These findings have yet to be confirmed with regards to natural infection. Why is SARS-CoV-2 more infectious than SARS-CoV-1?SARS-CoV-2 has a higher reproductive number (R0) than SARS-CoV-1, indicating much more efficient spread.1 Several characteristics of SARS-CoV-2 may help explain this enhanced transmission. While both SARS-CoV-1 and SARS-CoV-2 preferentially interact with the angiotensin-converting enzyme 2 (ACE 2) receptor, SARS-CoV-2 has structural differences in its surface proteins that enable stronger binding to the ACE 2 receptor4 and greater efficiency at invading host cells.1 SARS-CoV-2 also has greater affinity (or bonding) for the upper respiratory tract and conjunctiva,5 thus can infect the upper respiratory tract and conduct airways more easily.6 Viral load dynamics and duration of infectiousnessViral load kinetics could also explain some of the differences between SARS-CoV-2 and SARS-CoV-1. In the respiratory tract, peak SARS-CoV-2 load is observed at the time of symptom onset or in the first week of illness with subsequent decline thereafter, which indicates the highest infectiousness potential just before or within the first five days of symptom onset (fig 2).7 In contrast, in SARS-CoV-1 the highest viral loads were detected in the upper respiratory tract in the second week of illness, which explains its minimal contagiousness in the first week after symptom onset, enabling early case detection in the community.7  Fig 2 After the initial exposure, patients typically develop symptoms within 5-6 days (incubation period). SARS-CoV-2 generates a diverse range of clinical manifestations, ranging from mild infection to severe disease accompanied by high mortality. In patients with mild infection, initial host immune response is capable of controlling the infection. In severe disease, excessive immune response leads to organ damage, intensive care admission, or death. The viral load peaks in the first week of infection, declines thereafter gradually, while the antibody response gradually increases and is often detectable by day 14 (figure adapted with permission from doi:10.1016/j.cell.2020.04.013; doi:10.1016/S2213-2600(20)30230-7) Quantitative reverse transcription polymerase chain reaction (qRT-PCR) technology can detect viral SARS-CoV-2 RNA in the upper respiratory tract for a mean of 17 days (maximum 83 days) after symptom onset.7 However, detection of viral RNA by qRT-PCR does not necessarily equate to infectiousness, and viral culture from PCR positive upper respiratory tract samples has been rarely positive beyond nine days of illness.5 This corresponds to what is known about transmission based on contact tracing studies, which is that transmission capacity is maximal in the first week of illness, and that transmission after this period has not been documented.8 Severely ill or immune-compromised patients may have relatively prolonged virus shedding, and some patients may have intermittent RNA shedding; however, low level results close to the detection limit may not constitute infectious viral particles. While asymptomatic individuals (those with no symptoms throughout the infection) can transmit the infection, their relative degree of infectiousness seems to be limited.91011 People with mild symptoms (paucisymptomatic) and those whose symptom have not yet appeared still carry large amounts of virus in the upper respiratory tract, which might contribute to the easy and rapid spread of SARS-CoV-2.7 Symptomatic and pre-symptomatic transmission (one to two days before symptom onset) is likely to play a greater role in the spread of SARS-CoV-2.1012 A combination of preventive measures, such as physical distancing and testing, tracing, and self-isolation, continue to be needed. Route of transmission and transmission dynamicsLike other coronaviruses, the primary mechanism of transmission of SARS-CoV-2 is via infected respiratory droplets, with viral infection occurring by direct or indirect contact with nasal, conjunctival, or oral mucosa. Target host receptors are found mainly in the human respiratory tract epithelium, including the oropharynx and upper airway. The conjunctiva and gastrointestinal tracts are also susceptible to infection and may serve as transmission portals.6 Transmission risk depends on factors such as contact pattern, environment, infectiousness of the host, and socioeconomic factors, as described elsewhere.12 Most transmission occurs through close range contact (15 minutes face to face and within 2 m),13 and spread is especially efficient within households and through gatherings of family and friends.12 Household secondary attack rates (the proportion of susceptible individuals who become infected within a group of susceptible contacts with a primary case) ranges from 4% to 35%.12 Sleeping in the same room as, or being a spouse of an infected individual increases the risk of infection, but isolation of the infected person away from the family is related to lower risk of infection.12 Other activities identified as high risk include dining in close proximity with the infected person, sharing food, and taking part in group activities 12 The risk of infection substantially increases in enclosed environments compared with outdoor settings.12 Aerosol transmission can still factor during prolonged stay in crowded, poorly ventilated indoor settings (meaning transmission could occur at a distance >2 m).12141516 The role of faecal shedding in SARS-CoV-2 transmission and the extent of fomite (through inanimate surfaces) transmission also remain to be fully understood. Both SARS-CoV-2 and SARS-CoV-1 remain viable for many days on smooth surfaces (stainless steel, plastic, glass) and at lower temperature and humidity (eg, air conditioned environments).1718 Thus, transferring infection from contaminated surfaces to the mucosa of eyes, nose, and mouth via unwashed hands is a possible route of transmission. This route of transmission may contribute especially in facilities with communal areas, with increased likelihood of environmental contamination. However, both SARS-CoV-1 and SARS-CoV-2 are readily inactivated by commonly used disinfectants, emphasising the potential value of surface cleaning and handwashing. SARS-CoV-2 RNA has been found in stool samples and RNA shedding often persists for longer than in respiratory samples7; however, virus isolation has rarely been successful from the stool.57 No published reports describe faecal-oral transmission. In SARS-CoV-1, faecal-oral transmission was not considered to occur in most circumstances; but, one explosive outbreak was attributed to aerosolisation and spread of the virus across an apartment block via a faulty sewage system.19 It remains to be seen if similar transmission may occur with SARS-CoV-2. PathogenesisViral entry and interaction with target cellsSARS-CoV-2 binds to ACE 2, the host target cell receptor.1 Active replication and release of the virus in the lung cells lead to non-specific symptoms such as fever, myalgia, headache, and respiratory symptoms.1 In an experimental hamster model, the virus causes transient damage to the cells in the olfactory epithelium, leading to olfactory dysfunction, which may explain temporary loss of taste and smell commonly seen in covid-19.20 The distribution of ACE 2 receptors in different tissues may explain the sites of infection and patient symptoms. For example, the ACE 2 receptor is found on the epithelium of other organs such as the intestine and endothelial cells in the kidney and blood vessels, which may explain gastrointestinal symptoms and cardiovascular complications.21 Lymphocytic endotheliitis has been observed in postmortem pathology examination of the lung, heart, kidney, and liver as well as liver cell necrosis and myocardial infarction in patients who died of covid-19.122 These findings indicate that the virus directly affects many organs, as was seen in SARS-CoV-1 and influenzae. Much remains unknown. Are the pathological changes in the respiratory tract or endothelial dysfunction the result of direct viral infection, cytokine dysregulation, coagulopathy, or are they multifactorial? And does direct viral invasion or coagulopathy directly contribute to some of the ischaemic complications such as ischaemic infarcts? These and more, will require further work to elucidate. Immune response and disease spectrum (figure 2)After viral entry, the initial inflammatory response attracts virus-specific T cells to the site of infection, where the infected cells are eliminated before the virus spreads, leading to recovery in most people.23 In patients who develop severe disease, SARS-CoV-2 elicits an aberrant host immune response.2324 For example, postmortem histology of lung tissues of patients who died of covid-19 have confirmed the inflammatory nature of the injury, with features of bilateral diffuse alveolar damage, hyaline-membrane formation, interstitial mononuclear inflammatory infiltrates, and desquamation consistent with acute respiratory distress syndrome (ARDS), and is similar to the lung pathology seen in severe Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS).2526 A distinctive feature of covid-19 is the presence of mucus plugs with fibrinous exudate in the respiratory tract, which may explain the severity of covid-19 even in young adults.27 This is potentially caused by the overproduction of pro-inflammatory cytokines that accumulate in the lungs, eventually damaging the lung parenchyma.23 Some patients also experience septic shock and multi-organ dysfunction.23 For example, the cardiovascular system is often involved early in covid-19 disease and is reflected in the release of highly sensitive troponin and natriuretic peptides.28 Consistent with the clinical context of coagulopathy, focal intra-alveolar haemorrhage and presence of platelet-fibrin thrombi in small arterial vessels is also seen.26 Cytokines normally mediate and regulate immunity, inflammation, and haematopoiesis; however, further exacerbation of immune reaction and accumulation of cytokines in other organs in some patients may cause extensive tissue damage, or a cytokine release syndrome (cytokine storm), resulting in capillary leak, thrombus formation, and organ dysfunction.2329 Mechanisms underlying the diverse clinical outcomesClinical outcomes are influenced by host factors such as older age, male sex, and underlying medical conditions,1 as well as factors related to the virus (such as viral load kinetics), host-immune response, and potential cross-reactive immune memory from previous exposure to seasonal coronaviruses (box 1). Box 1 Risk factors associated with the development of severe disease, admission to intensive care unit, and mortalityUnderlying conditionPresentationLaboratory markersSex-related differences in immune response have been reported, revealing that men had higher plasma innate immune cytokines and chemokines at baseline than women.30 In contrast, women had notably more robust T cell activation than men, and among male participants T cell activation declined with age, which was sustained among female patients. These findings suggest that adaptive immune response may be important in defining the clinical outcome as older age and male sex is associated with increased risk of severe disease and mortality. Increased levels of pro-inflammatory cytokines correlate with severe pneumonia and increased ground glass opacities within the lungs.2931 In people with severe illness, increased plasma concentrations of inflammatory cytokines and biomarkers were observed compared with people with non-severe illness.293233 Emerging evidence suggests a correlation between viral dynamics, the severity of illness, and disease outcome.7 Longitudinal characteristics of immune response show a correlation between the severity of illness, viral load, and IFN- α, IFN-γ, and TNF-α response.33 In the same study many interferons, cytokines, and chemokines were elevated early in disease for patients who had severe disease and higher viral loads. This emphasises that viral load may drive these cytokines and the possible pathological roles associated with the host defence factors. This is in keeping with the pathogenesis of influenza, SARS, and MERS whereby prolonged viral shedding was also associated with severity of illness.734 Given the substantial role of the immune response in determining clinical outcomes, several immunosuppressive therapies aimed at limiting immune-mediated damage are currently in various phases of development (table 1). Table 1 Therapeutics currently under investigation View this table: Immune response to the virus and its role in protectionCovid-19 leads to an antibody response to a range of viral proteins, but the spike (S) protein and nucleocapsid are those most often used in serological diagnosis. Few antibodies are detectable in the first four days of illness, but patients progressively develop them, with most achieving a detectable response after four weeks.35 A wide range of virus-neutralising antibodies have been reported, and emerging evidence suggests that these may correlate with severity but wane over time.36 The duration and protectivity of antibody and T cell responses remain to be defined through studies with longer follow-up. CD-4 T cell responses to endemic human coronaviruses appear to manifest cross-reactivity with SARS-CoV-2, but their role in protection remains unclear.37 Unanswered questionsFurther understanding of the pathogenesis for SARS-CoV-2 will be vital in developing therapeutics, vaccines, and supportive care modalities in the treatment of covid-19. More data are needed to understand the determinants of healthy versus dysfunctional response and immune markers for protection and the severity of disease. Neutralising antibodies are potential correlates of protection, but other protective antibody mechanisms may exist. Similarly, the protective role of T cell immunity and duration of both antibody and T cell responses and the correlates of protection need to be defined. In addition, we need optimal testing systems and technologies to support and inform early detection and clinical management of infection. Greater understanding is needed regarding the long term consequences following acute illness and multisystem inflammatory disease, especially in children. Education into practiceHow would you describe SARS-CoV-2 transmission routes and ways to prevent infection? How would you describe to a patient why cough, anosmia, and fever occur in covid-19? Questions for future research
How patients were involved in the creation of this articleNo patients were directly involved in the creation of this article. How this article was createdWe searched PubMed from 2000 to 18 September 2020, limited to publications in English. Our search strategy used a combination of key words including "COVID-19," "SARS-CoV-2," "SARS", "MERS," "Coronavirus," "Novel Coronavirus," "Pathogenesis," "Transmission," "Cytokine Release," "immune response," "antibody response." These sources were supplemented with systematic reviews. We also reviewed technical documents produced by the Centers for Disease Control and Prevention and World Health Organization technical documents. Footnotes
This article is made freely available for use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained. https://bmj.com/coronavirus/usage | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Posted: 20 Oct 2020 12:34 AM PDT Abbreviations
1 INTRODUCTIONCoronavirus disease 2019 (COVID‐19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) virus, was first reported in December 2019, with the first likely case recorded in Wuhan, China (Lescure et al., 2020). Since this time, the virus has spread to more than 200 countries, with over 33 million confirmed cases and 1,009,270 deaths as of October 1, 2020 (https://covid19.who.int/). COVID‐19 is thought to spread mainly through respiratory droplets and close contact, and it displays a relatively high basic reproduction number (R0) value estimated between 2.2 and 5.7. This high infection potential combined with a delay in visible symptoms for up to 2 weeks has enabled this virus to spread rapidly into pandemic proportions (Cui et al., 2019; Sanche et al., 2020). Due to these extreme circumstances, great effort has been made to develop diagnostic tools and treatment options for the virus. At the time of this writing, real‐time quantitative polymerase chain reaction (RT‐qPCR)‐based assays are the diagnostic standard for coronavirus testing; however, immunoassays and other technologies are rapidly being developed and deployed (Cheng et al., 2020). Data from testing suggest that age and the presence of comorbidities, which include cardiovascular disease, obesity, cancer, and diabetes, are major risk factors in COVID‐19 fatality (Onder et al., 2020). These risk factors pose major challenges to COVID‐19 treatment, as increased isolation and more stringent testing and therapeutics are necessary in the case of comorbidity (Wu et al., 2020). The virus itself poses major clinical challenges. It has created a large patient load that threatens to overwhelm healthcare systems and treatment demands, the use of critical supplies, such as ventilators, large‐scale personal protective equipment usage, and basic medical supplies (Ranney et al., 2020). The concurrent disruption of global supply chains facilitates this critical need. Along with the equipment challenges, the immediate patient burden stretches all normal supplies thin and limits healthcare availability for the general population and prevents noncritical surgeries from being performed due to the risk of contamination (Cohen et al., 2020). These challenges make it critical for effective clinical treatments to be developed, to lessen the burden on stressed healthcare systems (Hatswell, 2020). In this review, we describe in brief about the virus properties, COVID‐19 pathogenesis specifically focusing on sepsis and heart, and available treatment options. 2 SARS‐CoV‐2 INFECTIVITY CHARACTERISTICSSARS‐CoV‐2 is an enveloped, single‐stranded, positive‐sense ribonucleic acid (RNA) virus (Figure 1) that belongs to the β‐coronavirus family of viruses, which is capable of infecting humans and animals (Shereen et al., 2020). Several members of this virus family have been known to infect humans with mild symptoms and are self‐limiting (Andersen et al., 2020). Interestingly, SARS‐CoV‐2 is closely related to SARS‐CoV (severe acute respiratory syndrome virus: 82% homology) and MERS‐CoV (Middle Eastern respiratory syndrome virus: 50% homology) that cause respiratory disease and were responsible for outbreaks in 2003 (China) and 2012 (Middle East), respectively. Although the evolution of these viruses has become a very hot topic, these viruses undergo gene recombination, insertions, and deletions, making them easy to mutate, manipulate, and transmit from one species to another (Luo et al., 2018). Consistent with the above report, several studies using in vitro cell culture and mouse models have shown the potential for the emergence of COVID‐like viruses (Menachery et al., 2015).  SARS‐CoV‐2 virus. Structure and genomic organization of SARS‐CoV‐2. (A) A SARS‐CoV‐2 particle comprises of spike glycoprotein (S), small envelop protein (E), and membrane glycoprotein (M) embedded in a lipid bilayer that encloses a single‐stranded RNA genome and nucleocapsid protein (N). (B) SARS‐CoV‐2 genome is a positive‐sense single‐stranded RNA of approximately 30‐kb size. The viral genome consists of the 5′‐untranslated region (5′‐UTR) at the N‐terminal, ORF 1a and ORF 1b encoding for nonstructural proteins, structural proteins including spike (S), envelop (E), membrane (M), and nucleocapsid (N), as well as 3′‐UTR at the C‐terminal. The expanded view of spike protein shows S1 and S2 subunits with a 12‐nucleotide insertion at S1–S2 junction, which is targeted by host furins/transmembrane proteases Virus gains entry inside the cell through angiotensin‐converting enzyme 2 (ACE2) receptors (Lan et al., 2020; Wan et al., 2020). Once inside the cells, its RNA is released and transcribed to virus proteins (mainly nonstructural proteins). In the late phase, virus structural proteins are transcribed that are used for virus repackaging and release (Figure 2; Shereen et al., 2020). There are several important characteristics of this virus that make it unique. (1) It is an enveloped virus with a lipid bilayer, thus making it very stable in the environment (72 h on plastic and 3 h in aerosols; van Doremalen et al., 2020) and also easy to inactivate using routine sanitizers. (2) It is highly infectious, and this increase in infectivity is due to unique sequences in the spike protein that enhances its affinity to its receptor by several folds (discussed below). (3) The virus is present in the saliva of infected individuals, and thus present in the droplets while talking and singing aloud, coughing, and sneezing. (4) It is less pathogenic; thus, 25%–50% of people are asymptomatic. (5) This virus can infect animals (mainly cats) as well. Therefore, it poses a major challenge for preventing virus spread.  SARS‐CoV‐2 replication. Lifecycle of SARS‐CoV‐2. SARS‐CoV‐2 enters cells via the interaction of spike protein with ACE2 present on the surface of cells. Once inside the cells, it releases its genomic RNA into the cytoplasm. The viral genome uses the host machinery to translate into polyproteins that are further proteolyzed into smaller proteins by viral proteinases. Discontinuous transcription of the positive‐strand RNA results in the synthesis of subgenomic negative‐strand RNA, which is translated into viral structural proteins and serves as a template for the replication of genomic RNA. Genomic RNA and nucleocapsid protein together form a nucleoprotein complex in the cytoplasm and are assembled with other structural proteins, such as spike (S), envelop (E), and membrane (M) proteins, into the ER−Golgi intermediated compartment (ERGIC). New virus particles are released through exocytosis. The link between viral nonstructural proteins and the Rab pathway may lead to exosome‐mediated dissemination of the viral modulators and inflammatory mediators, which needs to be explored As mentioned above, virus spike protein is very key to its infectivity. The virus genomic sequence analysis has identified several insertions and mutations in the spike gene; therefore, it may have diverged from other related viruses, such as SARS‐CoV, MERS‐CoV, RaTG13, and Pangolin coronavirus (Andersen et al., 2020). Interestingly, the structure–function analysis by crystallography and binding studies has identified that SARS‐CoV‐2 spike protein has a very high affinity for ACE2 receptor (10–20‐fold higher than SARS‐CoV; Wrapp et al., 2020). Also, the insertion of four amino acids (RRAR) in the spike gene at S1–S2 junction is targeted by host furins and transmembrane protease serine 2 (Figure 1), and other proteases that promote virus fusion, thus increasing the infectivity of the virus (Coutard et al., 2020; Hoffmann et al., 2020). Interestingly, the presence of these motifs has been associated with increased pathogenicity in several viruses, including H5N1, MERS, and others (Coutard et al., 2020). It is also intriguing that even with high sequence homology, similar structure, and affinity for the ACE2 receptor between SARS‐CoV and SARS‐CoV‐2 spike protein, none of the antibodies available for the SARS spike protein can neutralize SARS‐CoV‐2 virus (National Institutes of Health). This could be largely due to the insertion and several other mutations in the SARS‐CoV‐2. 3 PATHOGENESIS OF COVID‐19: THE SEPSIS LINKCOVID‐19 is a highly contagious respiratory syndrome, which can cause multiorgan failure that can lead to death in a small percentage of infections. It is transmitted from person to person by direct contact, through droplet infection, fecal–oral transmission, and aerosol. The virus can replicate in a wide range of cells that express ACE2, including nasal epithelium, nasopharynx, upper respiratory tract, type II pneumocytes in the lung, gastrointestinal (GI) tract, immune cells, and endothelium (Kumar et al., 2020; Sungnak et al., 2020). Due to the wide range of target cells, pathological symptoms and lesions are spread across different organs (Table 1). The severity of the disease also depends on risk factors and pre‐existing health conditions. Advanced age is a major risk factor, followed by hypertension, diabetes, obesity, chronic respiratory conditions, including chronic obstructive pulmonary disease and asthma, heart diseases, and immune status (Fang et al., 2020; Center for Disease Control). In the United States, African Americans are affected disproportionately as compared with other races. However, underlying mechanisms remain unknown. A recent study has identified extensive pulmonary thrombosis, microcoagulopathy in small vessels, hemorrhage, diffuse alveolar damage accompanied by intracardial necrosis, and right ventricle dilation among African Americans during autopsies (Fox et al., 2020). These findings were consistent with other studies; therefore, pre‐existing cardiac risk factors have been suggested to be the possible causes (McGonagle et al., 2020). However, African Americans have a higher incidence of several health conditions, such as hypertension, obesity, and diabetes, which are known risk factors for heart diseases; therefore they might be prone to the severity of the disease. Interestingly, the proarrhythmic variant p.Ser1103Tyr‐SCN5A, which is highly prevalent among African Americans and is associated with ventricular arrhythmia causing sudden cardiac death under hypoxic conditions, may also be responsible for increased fatalities (Giudicessi et al., 2020). Also, the human leukocyte antigen (HLA) gene and ACE2 gene polymorphisms (Hussain et al., 2020) have been suggested to affect the severity of the disease.
ACE2 signaling has also attracted a lot of attention, given the fact that the ACE2/Ang1‐7/Mas axis is crucial in regulating blood pressure, inflammation, fibrosis, thrombosis, etc. (Santos et al., 2003; Simões e Silva et al., 2013). As a key mode of internalization, the downregulation or shedding of ACE2 after the virus entry has been reported in SARS‐CoV (Glowacka et al., 2010; Kuba et al., 2005), NL63 (Dijkman et al., 2012), and H5N1 (Zou et al., 2014), and a similar outcome is speculated in the SARS‐CoV‐2 infection. The downregulation of ACE2 in the infected organs could interfere with the ACE2/Ang1‐7/Mas axis, resulting in activated AngII and renin–angiotensin–aldosterone system, which is supposedly one of the plausible causes of COVID‐19‐associated alveolar inflammation and lung injury (Kai & Kai, 2020; Verdecchia et al., 2020). After entry through ACE2 receptors, the virus sheds its genome into the cytoplasm, which is transcribed to early viral proteins that play a critical role in the suppression of host immune response, tissue damage, and enhance viral genome replication. Structural proteins are transcribed in the late phase of viral replication to repackage and release virus particles (Figure 2). The interactome analysis of all the viral proteins has revealed that viral proteins target host cell nuclear export, integrated stress response system, RNA processing, mitochondrial functions, and cell death signaling (Gordon et al., 2020). During the virus replication, host cells activate antiviral immune response through major histocompatibility complex class I antigen presentation. This is followed by either an effective immune response to clear the virus infection or immune dysregulation that leads to a severe form of the disease. An effective antiviral response involves activation of both (i) cell‐mediated antiviral immunity through activation of CD8+ T cells, natural killer cells, and monocytes that target virus‐infected cells, and (ii) humoral immunity mediated by production of virus‐neutralizing antibodies, such as IgG and IgM, by CD27hiCD38hi cells and activated ICOS + PD‐1 + follicular helper T cells–TFH cells (CD4+ and CXCR5+ cells; Figure 3; Thevarajan et al., 2020).  SARS‐CoV‐2 pathogenesis. Mechanism of SARS‐CoV‐2‐induced cardiovascular disease, role of sepsis, and exosomes. SARS‐CoV‐2 is capable of infecting multiple organs due to the widespread expression of ACE2 receptors. During viral replication inside cells, the immune system is activated through MHC class I antigen presentation, which is followed by effective antiviral immunity, leading to recovery. However, in certain individuals, immune dysregulation results in cytokine storm and dissemination of virus in the body that might lead to sepsis. The virus can also infect endothelial cells that line the blood vessels, leading to endothelialitis and disseminated intravascular coagulation, which limits gas exchange in the lungs and causes metabolic acidosis. Sepsis caused by cytokine storm, virus, exosomes, hypoxemia, and disseminated intravascular coagulation may lead to multiple organ failure and death Individuals who do not recover, suffer acute respiratory syndrome, hypotension, and multiple organ failure (Xu et al., 2020). Laboratory findings showed high levels of fibrin degradation product D‐dimer (indicative of abnormal clotting; Zhou et al., 2020), lymphopenia (decrease in the number of lymphocytes; Chan et al., 2020), increased neutrophil count (Liu et al., 2020), and cytokine storm (Mehta et al., 2020) that is suggestive of sepsis. Interestingly, the culture of lung fluids did not yield bacterial growth (Fox et al., 2020; Li et al., 2020). Therefore, sepsis is likely caused by the virus itself (Li et al., 2020) that might lead to (i) immune dysregulation leading to cytokine storm, (ii) respiratory dysfunction leading to hypoxemia, and (iii) metabolic acidosis due to circulatory dysfunction (Figure 3). Cytokine storm is characterized by an increased production of cytokines, mainly IL‐6, C‐reactive protein (CRP), TNF‐α, IL‐1β, IL‐33, IFNγ, GMCSF, and others (Mehta et al., 2020). In addition, virus‐infected cells (type II pneumocytes, endothelial cells, etc.) could be the source of cytokines and toxins. Virus particles have also been demonstrated in endothelial cells from blood vessels (Varga et al., 2020) that may be responsible for microvascular dysfunction. Therefore, it is hypothesized that virus‐induced endothelial dysfunction may be promoting disseminated intravascular coagulation that limits blood flow and prevent oxygenation in the lungs (Figure 3). Hypoxia, due to an acute respiratory syndrome, along with metabolic acidosis due to poor circulation and microvascular dysfunction, may partly explain the cause of multiple organ dysfunction (such as heart, kidney, and liver; Figure 3). Although the cause and sources of cytokine storm, lymphopenia, and abnormal clotting are not known, activated immune cells and lymphocyte exhaustion have been suggested (Zhou et al., 2020). However, it should be noted that the cytokine storm is also observed in SARS and MERS infections. Whereas in SARS, it is attributed to exaggerated cytokine production by virus‐infected alveolar endothelial cells, dendritic cells, and macrophages, in MERS, it is attributed to lung infiltrating neutrophils, macrophages, and peripheral blood mononuclear cells (Channappanavar & Perlman, 2017). Interestingly, the transcriptomic analysis of bronchial alveolar fluid, peripheral blood mononuclear cells from COVID‐19 human patients, and ferret models and in vitro cell lines revealed poor antiviral responses lacking IFNI and III responses (Blanco‐Melo et al., 2020; Gardinassi et al., 2020), which may partly explain asymptomatic and prolonged infection. These studies also revealed interferon‐specific gene signatures, activation of neutrophils, and poor response from dendritic cells and macrophages. Furthermore, recent studies by different groups showed the presence of T cells reactive to SARS‐CoV‐2 peptide antigens in people who have not been infected with the virus, which has been attributed to exposure to coronavirus that causes common cold (Grifoni et al., 2020; Moreno et al., 2020; Premkumar et al., 2020). However, their role in pathogenesis and development of immunity remains to be seen (Sette & Crotty, 2020). In addition, future research identifying the root cause of the cytokine storm will help treat COVID‐19 complications. Likewise, the cause of the severity of the disease in the presence of other comorbidities is unknown. However, it is well known from the literature that inflammation is upregulated in most of these cardiovascular and metabolic diseases characterized by an increase in CRP, TNF‐α, and IL‐6 levels. Therefore, we speculate that the immune system is primed for overactivation under COVID‐19 infection in these individuals. 4 EXOSOME LINK TO COVID‐19 PATHOGENESISExosomes are nanoscale extracellular double‐membrane vesicles secreted by cells that have emerged as novel intercellular communicators. Exosomes are actively secreted by the endolysosomal system and carry messages in the form of proteins, enzymes, cytokines, lipids, and RNA from donor cells to the target cells. Extensive research has shown that exosomes play a critical role in organ cross‐talk, maintaining tissue homeostasis, host–pathogen interactions, and pathophysiology of various diseases, including sepsis (Dykes, 2017; Kita et al., 2019; Sahoo & Losordo Douglas, 2014; Schorey et al., 2015). Likewise, virus infections exploit exosome pathway to gain entry, spread virus infection, virus packaging, evade host immune system, and pathogenesis (shown in Figure 4; virus pathogenesis using exosomes is summarized in Table 2; Alenquer & Amorim, 2015; Anderson et al., 2016; Urbanelli et al., 2019; Wurdinger et al., 2012). Due to similarities in pathways of exosome biogenesis (ESCRT‐dependent and independent), their fate (actively taken up by target cells by endocytosis, pinocytosis, and receptor‐mediated uptake) and virus uptake, packaging, and release, they were likened to be relatives (Nolte‐'t Hoen et al., 2016). Exosome‐mediated host immune modulation by viral infections has been extensively studied and has been reviewed elsewhere in detail (Schorey et al., 2015). Virus infections stimulate host cells to secrete exosomes that function as pathogen‐associated molecular patterns, carry inflammatory mediators, and cause inflammation (Schorey et al., 2015). For example, exosomes from EBV‐infected cells that are enriched in dUTPase induce activation of NF‐κB pathway and stimulate macrophage cytokine release (Ariza et al., 2013). Likewise, HCV mRNA in exosomes induces secretion of IFN alpha from macrophages and exosomes from C3/36 cells infected with Zika virus induce expression TNF alpha from monocytes and cause endothelial damage to induce intravascular coagulation and inflammation (Martínez‐Rojas et al., 2020). Exosomes from Kaposi sarcoma‐associated herpesvirus also cause endothelial damage and induce expression of IL6 (Chugh et al., 2013). Exosomes from virus‐infected cells also cause apoptosis of immune cells. For example, HIV infection induces secretion of exosomes that are enriched in viral Nef protein, which causes apoptosis of endothelial cells and CD4 T‐helper cells (Lenassi et al., 2010). Likewise, EBV‐infected cells secrete exosomes enriched with galactin9 that cause apoptosis of cytotoxic T cells specific to EBV‐infected cells (Dukers et al., 2000). In summary exosomes from virus‐infected cells can cause tissue injury by activating inflammation and cytotoxicity.  Hypothesized role of exosomes in SARS‐CoV‐2 pathogenesis. Exosomes derived from virus‐infected cells promote sepsis and tissue injury. Exosomes from virus‐infected cells are packaged with bioactive molecules, including miRs, viral proteins, inflammatory cytokines, cytotoxic agents, and lipids that incite inflammation, activate endothelium, and affect intravascular coagulation, leading to the sepsis‐like condition
Several important features of SARS‐CoV‐2 infection, mainly hyperactivated immune system to induce sepsis‐like disease characterized by cytokine storm and lymphopenia, raise the question concerning the involvement of exosomes (Figure 4). This idea is further strengthened by the TGN pathway (trans‐Golgi network, which is a part of the sorting system in the endolysosomal pathway) involvement in the replication of SARS‐CoV‐2. In addition, recent data showing the involvement of lipid metabolism including cholesterol metabolism (C. Zhang et al., 2020; X. J. Zhang et al., 2020) in the pathogenesis of COVID‐19 complications pose the question if exosomes are involved in the pathogenesis of SARS‐CoV‐2 infection. Consistent with this idea, the SARS‐CoV‐2 protein interactome analysis revealed the interaction with Rab proteins that are a part of the ESCRT pathway involved in exosome biogenesis. Interestingly, several viruses that exploit exosomes for pathogenesis interact with Rab proteins (Bello‐Morales et al., 2012; Fraile‐Ramos et al., 2010; Gerber et al., 2015). Moreover, high‐throughput lipidomics of sera from human patients revealed exosome‐specific lipid profiles that were enriched with sphingomyelins and gangliosides, and deficient in Di‐acyl glycerols (DAG). Interestingly, exosome enrichment with gangliosides (GM3) was strongly associated with the severity of the disease and likely cause of lymphopenia, as immune cells have a preference for GM3‐enriched exosomes, which are cytotoxic (J. W. Song et al., 2020; Y. Song et al., 2020). It should also be noted that SARS‐CoV‐2 is barely 8 months old and its understanding is evolving, and given the lack of strong antiviral immune response, as discussed before, the role of epigenetics mechanisms including miRs and other noncoding RNAs needs a full investigation. Moreover, extensive literature suggests that exosomes play an important role in shuttling of these noncoding RNAs between different cell types and have been implicated in the development of cardiovascular diseases. Interestingly, in a recent in vitro study, transduction of lung epithelial A549 cells with SARS‐CoV‐2 structural and nonstructural genes (excluding viral Spike protein) resulted in the secretion of exosomes enriched with viral RNAs. These exosomes were successfully taken up by the human‐induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs), which resulted in elevated inflammatory markers in hiPSC‐CMs along with the presence of viral genes (Kwon et al., 2020), allowing us to speculate the possible role of exosomes in the SARS‐CoV‐2 pathogenesis. This may also explain the possible mechanism of myocardial inflammation in COVID‐19 patients without direct viral infection that has puzzled the researchers. Consistent with this, given the extensive activation and inhibition of protein kinases by SARS‐CoV‐2 infection in cells (Bouhaddou et al., 2020), it is also possible that exosomes from virus‐infected cells may also carry proteins that can activate inflammatory response and cause tissue injury in distant organs. Therefore, it will be interesting to see if exosomes can be targeted for therapy, and future research using the exosome research tools will be helpful in addressing these possibilities. 5 COVID‐19 AND HEART5.1 Cardiac complications associated with COVID‐19 infectionAlthough the lungs and the respiratory tract are the most vulnerable tissues for SARS‐CoV‐2 infection (Zou et al., 2020), the virus also severely affects the pathophysiology of the heart. Several cardiac complications are associated with SARS‐CoV‐2 infection, which are summarized in Table 3 and Figure 5. Here, we discuss acute and chronic cardiac manifestations of COVID‐19.
 COVID‐19 and heart. Association between SARS‐CoV‐2 and heart pathophysiology. SARS‐CoV‐2 could affect cardiac physiology either directly via its interaction with ACE2 receptors or through other indirect mechanisms, including immune response, vascular coagulation, and oxygen deprivation. SARS‐CoV‐2 infection has been associated with cardiogenic shock, dysrhythmias, viral myocarditis, and acute myocardial injuries, leading to cardiac damage and fatal outcomes 5.2 DIrect myocardial injury: myocardial localization of SARS‐CoV‐2Due to the high abundance of ACE2, the heart is among high‐risk organs (Chen et al., 2020; Zou et al., 2020) affected by COVID‐19 and is speculated to harbor SARS‐CoV‐2 RNA possibly due to the extrapulmonary dissemination of the virus. A reduced ACE2 expression has been negatively correlated with various cardiac pathologies, such as hypertension, maladaptive cardiac remodeling, heart failure, and cardiomyopathies (Kassiri et al., 2009; Oudit et al., 2009; Patel et al., 2014, 2016). Also, as it is postulated that SARS‐CoV‐2 infection could result in ACE2 downregulation, this might affect the cardiac pathophysiology via differential regulation of the ACE2/Ang1‐7/Mas axis. The relationship between SARS‐CoV‐2, ACE2, and cardiovascular outcomes has been reviewed recently and could help to expend the knowledge horizon (J. Guo et al., 2020; South et al., 2020) Direct cardiac injury by SARS‐CoV‐2 is debatable; however, the presence of ACE2 in the heart poses a strong possibility of internalization of COVID‐19 by ACE2‐expressing cells in the heart. Out of 44 patients who died from SARS, a study examined the presence of the SARS‐CoV genome in the 20 autopsied heart tissues, revealing that 7 of the samples (35%) were found positive for the viral RNA. Moreover, myocardial localization of the viral particles was attributed to the expression of ACE2 in the heart (Oudit et al., 2009). Concerning the current coronavirus pandemic, very few reports have been published to confirm the myocardial infiltration of the SARS‐CoV‐2. Tavazzi et al. (2020) reported the first case of myocardial localization of SARS‐CoV‐2 in a 69‐year‐old patient who was diagnosed with acute myocardial injury, hypotension, and cardiogenic shock. Endomyocardial biopsy of the patient showed a low‐grade interstitial and endocardial inflammation along with virus particles present in the interstitial cells; however, the biopsy did not confirm the presence of coronavirus particles in cardiomyocytes or endothelial cells. Myocardial localization of COVID‐19 could imply the viremic phase or migration of infected macrophages to the heart and possibly other tissues. Exosome‐mediated dissemination of SARS‐CoV‐2 and viral genome/protein could also be of scientific interest and requires further exploration. As discussed in the previous section, recent evidence also pointed toward the exosomal transfer of SARS‐CoV‐2 genes to cardiomyocytes, which resulted in increased inflammation in these cells (Kwon et al., 2020). Many viruses share common endocytic signaling mechanisms and have been shown to exploit the exosomal machinery for their transmission and infection (Alenquer & Amorim, 2015; Izquierdo‐Useros et al., 2010; Ramakrishnaiah et al. 2013). The field of SARS viruses is evolving, and exploring the involvement of exosomes could help better understand the pathological mechanisms and develop therapeutics. In another study, the postmortem pathological examination of the heart biopsies of COVID‐19 patients (Tian et al., 2020) revealed focal edema, myocardial hypertrophy, and interstitial fibrosis; however, these features were linked to pre‐existing cardiac conditions rather than acute injury due to COVID‐19 infection. Although no apparent infiltration of inflammatory cells was observed in the heart, the real‐time PCR analysis showed the SARS‐CoV‐2 genome in one of the two heart biopsies. Overall, these findings indicate the existence of the SARS‐CoV‐2 (or its genome) in the heart, either through direct infection or disseminated by migrating cells or through exosomes, which might ultimately exert pathological changes in the myocardium. However, the lack of conclusive evidence necessitates further investigations to understand the direct effects of SARS‐CoV‐2 on the heart. 5.3 Role of inflammation in COVID‐19‐associated myocardial injuryAlthough direct myocardial injury via SARS‐CoV‐2 and ACE2 interaction is a strong possibility, COVID‐19‐associated cardiac damage is widely attributed to cytokine‐inflicted systemic and tissue inflammation. Dissemination of the virus into circulation through infected macrophages and other immune cells could lead to an exaggerated immune response and multiorgan dysfunction. One of the early reports describing myocardial inflammation in SARS‐CoV‐2 infection reported fulminant myocarditis with elevated IL‐6 levels along with other cardiac injury markers (troponin I, myoglobin, and N‐terminal brain natriuretic peptide; Zeng et al., 2020). Various cohort‐based studies also showed an increased cytokine production during COVID‐19 infection, and cytokine storm in these patients was found to be associated with the disease severity and patient survival (C. Huang et al., 2020; H. I. Huang et al., 2020; Zhou et al., 2020). Previously, it was found that immunological response in SARS patients is mainly mediated through the Th1‐cell activity (Wong et al., 2004) as opposed to SARS‐CoV‐2 infection, where an imbalance between both Th1 and Th2 activity was found to aggravate the inflammatory surge (C. Huang et al., 2020; H. I. Huang et al., 2020). Overall, evidence from the published studies so far implies that the SARS‐CoV‐2‐induced inflammatory surge is the plausible cause of organ damage in patients and could be targeted for therapeutic interventions. 5.4 Acute myocardial injuryIn SARS‐CoV‐2 patients, myocardial injury is evident from several factors, such as an increase in myocardial injury markers, echo and electrocardiographic abnormalities, cytokine storm, and myocarditis. Acute myocardial injury has been a critical and persistent feature in COVID‐19 patients. An earlier report showed that among 138 patients from Wuhan, China, admitted for SARS‐CoV‐2 infection, 7.2% of patients had an acute cardiac injury (D. Wang et al., 2020; J. Wang et al., 2020; T. Wang et al., 2020), and the cardiac injury was more prominent in the patients who needed intensive care unit (ICU) care than non‐ICU patients. In another case, 82 out of 416 hospitalized COVID‐19 patients (19.7%) had a cardiac injury (Shi et al., 2020) with elevated high‐sensitivity troponin I levels (median interquartile range: 0.19 vs. <0.006 μg/L in patients without cardiac injury). Cardiac injury patients also had a higher mortality rate than those without cardiac injury (51.2% vs. 4.5%). A retrospective cohort study of 191 patients from Wuhan, China, showed that 46% of nonsurvivors had a high‐sensitivity cardiac troponin I level, above the 99th percentile upper reference limit, as compared with 1% of survivors (Zhou et al., 2020). Increased levels of high‐sensitivity troponin are reported in most of the COVID‐19 patients with cardiac injury (T. Guo et al., 2020; Inciardi et al., 2020; Sala et al., 2020), making it a crucial diagnostic marker of myocardial injury in COVID‐19 patients. In addition to high‐sensitivity cardiac troponin, N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) is another important biomarker for myocardial stress in patients infected with SARS‐CoV‐2. Brain natriuretic peptide (BNP) and NT‐proBNP concentration increase in the circulation in response to cardiac impairment and changes in ventricle wall tension, and these molecules are widely used as biomarkers of heart failure (Bay et al., 2003; Hunt et al., 1997; Yasue et al., 1994). In the patients infected with coronavirus, an increased concentration of NT‐proBNP in circulation manifests myocardial injury and cardiac complications. A rise in NT‐proBNP has been reported in severe COVID‐19 cases associated with adverse clinical outcomes and poor prognosis (Gao et al., 2020; T. Guo et al., 2020; Inciardi et al., 2020; Zeng et al., 2020). Laboratory findings also showed an elevation in other cardiac injury markers, such as creatine kinase, lactate dehydrogenase, and CRP, in COVID‐19 patients (Du et al., 2020; Inciardi et al., 2020; Sala et al., 2020). 5.5 Chronic cardiac damage in COVID‐19 patientsThere is a scarcity of data on the long‐term implications of respiratory viruses associated with epidemics. The metabolic profiling of 25 SARS‐CoV survivors in a 12‐year follow‐up study showed dyslipidemia, altered glucose metabolism, and cardiovascular abnormalities (Wu et al., 2017). Another cohort‐based 10‐year follow‐up study showed an increased risk of cardiovascular complications in patients hospitalized for pneumonia (Corrales‐Medina et al., 2015). The structural similarity between SARS‐CoV and SARS‐CoV‐2 could predict long‐term cardiovascular damage. The long‐term effect of SARS‐CoV‐2 on the heart is addressed in two recently published German cohort‐based studies (Lindner et al., 2020; Puntmann et al., 2020). One study showed a high viral load of SARS‐CoV‐2 in the myocardium (above 1000 copies per μg RNA) of 41.0% of the patients (16 of 39 autopsied samples); however, this high viral load was not attributed to an inflammatory reaction, as no inflammatory cell infiltration was observed (Lindner et al., 2020). Similarly, an unselected cohort of 100 recovered patients revealed that 78% of the recovered patients had myocardial abnormalities, including myocardial inflammation, regional scars, and elevated injury markers (Puntmann et al., 2020). These findings necessitate the urgency of large cohort‐based follow‐up studies on recovered patients to evaluate the long‐term effect of SARS‐CoV‐2 on the cardiovascular system. 6 POTENTIAL THERAPEUTIC STRATEGIES AGAINST SARS‐CoV‐2 OR ITS COMPLICATIONSAs COVID‐19 is an infectious disease, vaccination is the best choice to prevent infection. However, this virus is just 10 months old; therefore, vaccine production and their validation, in terms of safety and protection, may take longer than the expected time. Fortunately, several vaccines are in production, and early testing has started in humans and macaques with RNA‐1273 (Moderna), ChAdOx1 (Oxford), BNT162b2 (Pfizer), Ad26.COV2‐S (Johnson and Johnson), and many others have shown promising results and are in advanced stages of clinical trials. Also, very little is known about the immunogenic antigen from SARS‐CoV‐2 that is important for activating protective immunity. Therefore, given the pandemic nature of COVID‐19, current strategies involve repurposing of existing drugs to control infection in the body and symptomatic treatments to mitigate the complications. 7 ANTIVIRAL THERAPYSARS‐CoV‐2 emerged in December 2019; it is barely 10 months old, and there is a scarcity of data about the virus. Therefore, the current strategy is related to repurposing of existing drugs on compassionate grounds to identify a drug that could help mitigate the virus infection. However, due to its close similarity with SARS and MERS viruses, several of the drugs that are in the pipeline for these viruses, as well as others like Ebola, have been used in clinical trials (summarized in Table 4, please note we have listed the drugs that are used alone or in combination). Data so far indicate that remdesivir, a nucleotide analog (adenosine) that is incorporated into viral RNA and inhibits its replication, has promising results in patients that are treated with the drug at a very early stage of infection (2–3 days of infection). Interestingly, remdesivir was originally developed to treat Ebola virus infection. Therefore, the repurposing of existing drugs is a way forward to find quick and timely treatment options. Also, the SARS‐CoV‐2 protein interactome analysis has identified several targets for which drugs are available in the developmental stage, which could provide novel avenues to treat virus infection (Gordon et al., 2020). Likewise, high‐throughput quantitative mass spectrometry‐based phosphoproteomics analysis of SARS‐CoV‐2‐infected Vero E6 cells identified strong activation of p38 MAP kinases, casein kinase II (CK2), Ca++ and calmodulin‐dependent kinases, PRKG1/2, and inhibition of cell cycle and cell growth kinases (Bouhaddou et al., 2020). Interestingly, inhibition of p38 MAP kinases, cyclin‐dependent kinase (CDK), AXL, and PIKFYVE kinases led to inhibition of virus replication in Vero and A549 cell lines (Bouhaddou et al., 2020), providing novel targets for antiviral drug development. In addition, monoclonal antibodies neutralizing viruses are also being developed and being tested. Antiviral immunotherapy using INF‐β as an aerosol in combination with lopinavir–ritonavir and ribavirin has also shown promising results in small trials. The triple therapy was effective in clearing the virus within 8 days in most of the patients (Hung et al., 2020). This may partly be explained by the poor antiviral response by the host; therefore, INF‐β might be very effective in activating the antivirus response.
8 PALLIATIVE/SYMPTOMATIC TREATMENTSAn extensive literature review suggests that the majority of the patients who progress to a severe form of the disease have sepsis‐like symptoms with coagulopathy and multiple organ dysfunction (D. Wang et al., 2020; J. Wang et al., 2020; T. Wang et al., 2020; Zhou et al., 2020). Therefore, it is logical to think if palliative therapy used in sepsis could be used in COVID‐19 patients. Interestingly, plasminogen inhalation therapy (that targets the clotting system) did show a dramatic improvement in respiratory function in a small set of patients (D. Wang et al., 2020; J. Wang et al., 2020; T. Wang et al., 2020). Interestingly, inhibitors of blood clotting are also used to treat sepsis patients in clinics. A recent study using dexamethasone, a good old synthetic long‐acting corticosteroid (RECOVERY Collaborative Group, 2020), and reports of Tocilizumab (IL6 inhibitor) for treating COVID‐19 complications suggest a dysfunctional immune system to be the cause of many complications. Likewise, given the fact that exosomes play a critical role in sepsis pathology (Essandoh et al., 2015; Raeven et al., 2018) and SARS‐CoV‐2 infection (J. W. Song et al., 2020; Y. Song et al., 2020), drugs targeting exosome pathways should be investigated in preclinical models. Interestingly, several drugs that target exosomes have been investigated for cancer and other diseases (reviewed in detail by Catalano & O'Driscoll (2020), summarized in Table 5); therefore, they should be investigated in preclinical studies to evaluate their efficacy as well as safety. In addition, mesenchymal stem cell‐derived exosomes could also be used for therapeutic purposes in COVID‐19 infection due to their immunomodulatory, anti‐inflammatory, and regenerative properties (reviewed elsewhere in detail [Akbari & Rezaie, 2020; Pinky et al., 2020]). We also suggest the investigation of ceramide synthesis inhibitors in preclinical studies, as exosome synthesis inhibitor targets this pathway (Essandoh et al., 2015). Also, ceramides have been known to activate inflammatory pathways in several metabolic and cardiovascular diseases (Bikman & Summers, 2011; Summers, 2018) that are known to have worse outcomes in COVID‐19. Therefore, targeting this pathway might have a synergistic effect in controlling sepsis, inflammation, and virus dissemination through circulation. Interestingly, Opaganib, a sphingosine kinase‐2 inhibitor, is undergoing clinical trials for treating pneumonia caused by SARS‐CoV‐2 (NCT04467840).
ACKNOWLEDGMENTThis study is supported, in part, by the National Institutes of Health (NIH) Grants HL138023 (to P. K. and J. Z.), the American Heart Association Transformational Project Award 19TPA34850100 (to P. K.), and T32 Training Grant T32EB023872 (to J. H.). CONFLICT OF INTERESTSThe authors declare that there are no conflict of interests.
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| Vitamin C and COVID-19: A Review - News-Medical.Net Posted: 22 Oct 2020 10:21 PM PDT Vitamin C, also known as ascorbic acid, is an essential water-soluble nutrient. Humans and a few other animals, such as primates, pigs, depend on vitamin C from the nutritional supply by fruits and vegetables (red peppers, oranges, strawberries, broccoli, mangoes, lemons). The potential role of vitamin C in preventing and ameliorating infection is well established in medical science. Ascorbic acid is crucial for immune responses. It has important anti-inflammatory, immunomodulating, antioxidant, antithrombotic, and antiviral properties. Vitamin C appears to favorably modulate host responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19) pandemic, especially in the critical stages. In a recent review published in Preprints*, Patrick Holford et al. address vitamin C's role as adjunctive therapy for respiratory infection, sepsis, and COVID-19.  This paper discusses the potential role of vitamin C in preventing the critical phase of COVID-19, acute respiratory infections, and other inflammatory diseases. Vitamin C supplementation could hold promise as a preventive or therapeutic agent for COVID-19 - to correct a disease-induced deficiency, reduce oxidative stress, enhance interferon production, and support the anti-inflammatory actions of glucocorticosteroids. To maintain a normal plasma level of 50 µmol/l in adults, a vitamin C dose of 90 mg/d for men and 80 mg/d for women is required. This is enough to prevent scurvy (a disease resulting from a lack of vitamin C). However, this level is inadequate for preventing viral exposure and physiological stress.
Vitamin C and immune responseA rapid decline in the human serum vitamin C levels is observed under conditions of physiological stress. A serum level of vitamin C ≤11 µmol/l is found in hospitalized patients - the majority of them suffering from acute respiratory infections, sepsis, or severe COVID-19. Various case studies reported from across the world demonstrate that low vitamin C levels are typical in critically- ill hospitalized patients, with both respiratory infections, pneumonia, sepsis, and COVID-19 - the most likely explanation being increased metabolic consumption. A meta-analysis highlights these observations: 1) risk of pneumonia is significantly reduced with vitamin C supplementation, 2) post-mortem investigations in COVID-19 deaths show a secondary pneumonia phenomenon, and 3) total pneumonia cohorts comprised 62% with hypovitaminosis C. Mechanism of action of vitamin CVitamin C has an important homeostatic role as an antioxidant. It is known to demonstrate direct virucidal activity and augment interferon production. It has effector mechanisms in both the innate and adaptive immune systems. Vitamin C lessens reactive oxidative species (ROS) and inflammation via attenuation of NF-κB activation. While SARS-CoV-2 downregulates the expression of type-1 interferons (the host's primary antiviral defense mechanism), ascorbic acid upregulates these key host defense proteins. Vitamin C's Relevance to COVID-19The critical and often fatal phase of COVID-19 occurs with the excessive generation of potent proinflammatory cytokines and chemokines. This results in the development of multi-organ failure. It is associated with neutrophil migration and accumulation within the lung interstitium and bronchioalveolar space - a key determinant of ARDS (Acute respiratory distress syndrome). Ascorbic acid concentrations are three to ten times higher in the adrenal glands and pituitary than in any other organ. Under conditions of physiological stress (ACTH stimulation), including viral exposure, vitamin C is released from the adrenal cortex resulting in a fivefold increase in plasma levels. Vitamin C enhances cortisol production and potentiates the anti-inflammatory and endothelial cytoprotective effects of glucocorticoids. Exogenous glucocorticoid steroids are the only proven treatment for COVID-19. Vitamin C, a pleiotropic stress hormone, plays a critical role in mediating the adrenocortical stress response, particularly in sepsis, and protecting the endothelium from oxidant injury. Colds are caused by over 100 different virus strains, some of which are coronaviruses. Given the effect of vitamin C on colds - reduced duration, severity, and the number of colds - vitamin C administration may reduce conversion from mild infection to the critical phase of COVID-19. Vitamin C supplementation is observed to reduce the length of ICU stay, shorten the ventilation time in critical COVID-19 patients, and reduce sepsis patients' mortality requiring vasopressor treatment. Vitamin C dosageThe authors discuss the safety of oral and intravenous administration of vitamin C, considering the various scenarios of diarrhea, kidney stones, and kidney failure during high dosages. A safe, short-term high dose of 2-8 g/day may be recommended (cautiously avoiding those with a history of kidney stones or kidney disease from high doses). Being water-soluble and thus excreted within hours, dose frequency is important to maintain sufficient blood levels during active infection. ConclusionVitamin C is known to avoid infections and improve immune responses. With specific reference to the critical phase of COVID- 19, vitamin C plays a critical role. It downregulates the cytokine storm, protects the endothelium from oxidant injury, has an essential role in tissue repair, and improves immune responses against infections. Vitamin C shows promising results when administered to the critically ill. The authors recommend that people in high-risk groups for COVID-19 mortality and at risk of vitamin C deficiency should be encouraged with vitamin C supplementation daily. They should ensure vitamin C adequacy at all times and increase the dose when virally infected to up to 6-8 g/day. Several dose-dependent vitamin C cohort studies are underway across the world to confirm its role in mitigating COVID-19 and better understand its role as therapeutic potential. *Important NoticePreprints publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information. Journal reference:
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| Single-cell analysis identified lung progenitor cells in COVID-19 patients - DocWire News Posted: 22 Oct 2020 11:00 PM PDT  Cell Prolif. 2020 Oct 22:e12931. doi: 10.1111/cpr.12931. Online ahead of print. ABSTRACT OBJECTIVES: The high mortality of severe 2019 novel coronavirus disease (COVID-19) cases is mainly caused by acute respiratory distress syndrome (ARDS), which is characterized by increased permeability of the alveolar epithelial barriers, pulmonary oedema and consequently inflammatory tissue damage. Some but not all patients showed full functional recovery after the devastating lung damage, and so far there is little knowledge about the lung repair process. We focused on crucial roles of lung progenitor cells in alveolar cell regeneration and epithelial barrier re-establishment and aimed to uncover a possible mechanism of lung repair after severe SARS-CoV-2 infection. MATERIALS AND METHODS: Bronchoalveolar lavage fluid (BALF) of COVID-19 patients was analysed by single-cell RNA-sequencing (scRNA-seq). Transplantation of a single KRT5+ cell-derived cell population into damaged mouse lung and time-course scRNA-seq analysis was performed. RESULTS: In severe (or critical) COVID-19 patients, there is a remarkable expansion of TM4SF1+ and KRT5+ lung progenitor cells. The two distinct populations of progenitor cells could play crucial roles in alveolar cell regeneration and epithelial barrier re-establishment, respectively. The transplanted KRT5+ progenitors could long-term engraft into host lung and differentiate into HOPX+ OCLN+ alveolar barrier cell which restored the epithelial barrier and efficiently prevented inflammatory cell infiltration. CONCLUSIONS: This work uncovered the mechanism by which various lung progenitor cells work in concert to prevent and replenish alveoli loss post-severe SARS-CoV-2 infection. PMID:33094537 | DOI:10.1111/cpr.12931 |
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