Emerging infectious diseases always pose a threat to humans along with plant and animal life. SARS-CoV2 is the recently emerged viral infection that originated from Wuhan city of the Republic of China in December 2019. Now, it has become a pandemic. Currently, SARS-CoV2 has infected more than 27.74 million people worldwide, and taken 901,928 human lives. It was named first ‘WH 1 Human CoV’ and later changed to 2019 novel CoV (2019-nCoV). Scientists have established it as a zoonotic viral disease emerged from Chinese horseshoe bats, which do not develop a severe infection. For example, Rhinolophus Chinese horseshoe bats harboring severe acute respiratory syndrome-related coronavirus (SARSr-CoV) or SARSr-Rh-BatCoV appear healthy and clear the virus within 2–4 months period. The article introduces first the concept of EIDs and some past EIDs, which have affected human life. Next section discusses mysteries regarding SARS-CoV2 origin, its evolution, and human transfer. Third section describes COVID-19 clinical symptoms and factors affecting susceptibility or resistance. The fourth section introduces the SARS-CoV2 entry in the host cell, its replication, and the establishment of productive infection. Section five describes the host’s immune response associated with asymptomatic, symptomatic, mild to moderate, and severe COVID-19. The subsequent seventh and eighth sections mention the immune status in COVID-19 convalescent patients and re-emergence of COVID-19 in them. Thereafter, the eighth section describes viral strategies to hijack the host antiviral immune response and generate the “cytokine storm”. The ninth section describes about transgenic humane ACE2 (hACE2) receptor expressing mice to study immunity, drugs, and vaccines. The article ends with the development of different immunomodulatory and immunotherapeutics strategies, including vaccines waiting for their approval in humans as prophylaxis or treatment measures.
The story of CoVs is not new to humans and they were first identified simultaneously in the UK and USA in early 1960s as the causal viruses for common cold and mild respiratory infections. However, they draw their attention following the emergence of SARS-CoV-induced severe acute respiratory syndrome (SARS) epidemic in 2002–2003. In 2014, another CoV-induced infection, called MERS emerged in the middle-eastern countries that spread to the UK, USA, and Canada. SARS and MERS have one thing in common that both emerged from bat CoV with different intermediate hosts. For example, masked palm civets and racoon dogs served as intermediate host for SARS and dromedary or Arabian camels for MERS-CoV. However, SARS-CoV2 has also originated from bats called horseshoe bats, but we still do not know the intermediated host from which the infection passed to humans and took the form of current pandemic. Hence, identifying the intermediate host will be beneficial to fight more specifically with the pandemic. For example, we can immunize those animals to prevent the future infection spread and also reveal the conditions, which lead to the evolution of the highly pathogenic SARS-CoV2 as the pathogenic evolution leading to the evolution of SARS-CoV2 has neither occurred in humans nor in bats as bats have closest CoV called RaTG13. However, we do not know about the common ancestor for RaTG13 and SARS-CoV2, whether that still exist, if yes in which intermediate host? Hence the chain of events leading to the SARS-CoV2 emergence and COVID-19 in humans should be discovered to efficiently deal with the virus. Studying evolution is key to investigate the emergence of biological processes, including infection and immunity.
Plenty of studies have divided patients in terms of symptoms varying form asymptomatic to mild to moderate to severe. Asymptomatic patients do not develop a robust pro-inflammatory innate immune response required to clear the infection, instead they harbor the virus, and serve as potent reservoirs and may spread infection for longer duration as compared to symptomatic individuals before recovery. Asymptomatic COVID-19 patients exhibit the NK and Th1 cells-dependent direct antiviral action agaisnt SARS-CoV2. However, active asymptomatic COVID-19 patients show an anti-inflammatory immune response (IL-13 and IL-10) and convalescent asymptomatic COVID-19 patients show weaker of Ab response that fades away very soon. They develop robust T cell memory response. The mechanisms behind this diverse immune response in asymptomatic active and convalescent COVID-19 patients should be explored. On the other hand, mild and moderate patient develop healthy and controlled immune response to clear the infection without its dysregulation as seen in severe COVID-19 patients. For example, in severe COVID-19 patients, virus hijacks the component of innate immune response (cGAS and RLR-mediated virus recognition, and the type 1 IFNs generation) which can directly recognize and kill it. But it, promotes the TLR7/TLR8-based pro-inflammatory immune response (cytokine storm), profound monocyte and neutrophil infiltration in the lungs to cause ALI or ARDS. Hence, only severe/critical COVID-19 patients lose life. Transgenic mice expressing hACE2 may serve as potential animals for studying SARS-CoV2 infection, immunity, and different drugs, including vaccines. However, a mutant SARS-CoV2MA can infect WT mice and can induce mild to moderate infection in younger mice and severe pneumonia in older mice. Thus we are entering in an era where animal model-based studies will provide unexplored immunological mechanisms.
For example, thalidomide is a potent immunomodulatory agent, and has been used in pneumonia and sepsis previously as an immunomodulatory drug. Even a recent, clinical study has indicated its immunomodulatory and protective action in sever COVID-19 patients as an adjuvant therapy with low‐dose short‐term glucocorticoid. Even currently, thalidomide is under phase II clinical trial for severe COVID-19 patients (ClinicalTrial.gov Identifier: NCT04273529). The immunomodulatory role of statins should also be studied in severe COVID-19 . In a recent study, the in hospital use of statins has decreased the mortality rate in COVID-19 patients due to its immunomodulatory action that decreased IL-6 levels and neutrophil count . The in vivo mechanism of thalidomide and statins in COVID-19 needs an exploration using transgenic hACE2 receptor expressing mice or mutant SARS-CoV2MA in WT mice.
Immune system has evolved to protect the host from pathogens and internal damage-associated molecular patterns (DAMPs). However, due to the novelty of the SARS-CoV2 it may be a difficult target for the human immune system causing a dysregulated immune response during COVID-19. For example, some develop asymptomatic infection and other develop severe disease causing increased mortality. Even the SARS-CoV2 has different factors or proteins, which hijack the direct antiviral defence machinery without affecting the pro-inflammatory cytokine release to induce cytokine storm. Hence, understanding the immunology of the COVID-19 or SARS-CoV2 infection is one of the several roads for the successful management of the infection. Now we have human ACE2 transgenic mice to use for immunology, immunopathogenesis, and therapeutics-based studies. Therapeutics are urgently needed to strengthen the immune system to accept the SARS-CoV2 challenge to the immune system that is “catch me if you can”.
Reference & Source information: ScienceDirect.com | Science, health and medical journals, full text articles and books.
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