Introduction - the perennial pandemic: It is being increasingly realised that the COVID-19 may have become the new reality associated with human existence world over and the mankind may have to live with it for years or even decades. Further, the grievous nature of the disease is evolving further with the genomic changes in the virus in form of mutations and evolution of variants, with enhanced infectivity and probably virulence. There are serious challenges posed by the SARS-CoV-2 virus and COVID-19 as the disease. COVID-19 as acute and chronic disease: On exposure to the SARS-CoV-2 virus, not all patients develop a disease. Further, for those who develop the disease, there is a large variation in disease severity. The known factors including the constituent factors and several still unknown factors influence the disease manifestations, its course, and later the convalescent phase as well. In fact, substantial continuing morbidity after resolution of the infection indicates persisting multisystem effects of COVID-19. The ‘long COVID-19’ or ‘long haulers’: The patients who continue to suffer with persisting symptoms have been described as long haulers and the clinical condition has been called post-COVID-19 or ‘long COVID-19’. The diagnosis should be entertained if various symptoms and signs linger well beyond the period of convalescence in COVID-19. With the chronicity, there occur inflammatory changes and damage in various organs, and the extent of organ damage determines the long-term effects. Management of ‘long COVID’ syndrome: The ‘long COVID’ syndrome has multi-system involvement, variable presentation, and unpredictable course. Following clinical and investigational assessment, the patients should be managed as per clinical manifestations, extent of organ damage and associated complications. The findings from various studies indicate that preventing further organ damage in ‘long COVID’ is crucial. The long COVID’s prognostic challenges: As apparent, the ‘long COVID’ afflictions are more common than realized earlier. The symptoms can escalate in patients with co-morbid conditions. The persistent symptoms among COVID-19 survivors pose new challenges to the healthcare providers and may be suitably managed with a combination of pharmacological and non-pharmacological treatments, and holistic healthcare.

Introduction: SARS-CoV-2 life cycle: The disease which reportedly began in Chinese city Wuhan in November-December 2019 manifesting as severe respiratory illness, soon spread to various parts of the world, and was named COVID-19, and declared a pandemic by WHO. The life cycle of SARS-CoV-2 begins with membrane fusion mediated by Spike (S) protein binding to the ACE2 receptors. Following viral entry and release of genome into the host cell cytoplasm there occurs replication and transcription to generate viral structural and non-structural proteins. Finally, VLPs are produced and the mature virions are released from the host cell. Immunogenicity of the spike protein: The S protein is considered the main antigenic component among structural proteins of SARS-CoV-2 and responsible for inducing the host immune response. The neutralising antibodies (nAbs) targeting the S protein are produced and may confer a protective immunity against the viral infection. Further, the role of the S protein in infectivity also makes it an important tool for diagnostic antigen-based testing and vaccine development. The S-specific antibodies, memory B and circulating TFH cells are consistently elicited following SARS-CoV-2 infection, and COVID-19 vaccine shots in clinical trials. The emerging SARS-CoV-2 variants: The early genomic variations in SARS-CoV-2 have gone almost unnoticed having lacked an impact on disease transmission or its clinical course. Some of the recently discovered mutations, however, have impact on transmissibility, infectivity, or immune response. One such mutation is the D614G variant, which has increased in prevalence to currently become the dominant variant world-over. Another, relatively new variant, named VUI-202012/01 or B.1.1.7 has acquired 17 genomic alterations and carries the risk of enhanced infectivity. Further, its potential impact on vaccine efficacy is a worrisome issue. Conclusion: THE UNMET CHALLENGES: COVID-19 as a disease and SARS-CoV-2 as its causative organism, continue to remain an enigma. While we continue to explore the agent factors, disease transmission dynamics, pathogenesis and clinical spectrum of the disease, and therapeutic modalities, the grievous nature of the disease has led to emergency authorizations for COVID-19 vaccines in various countries. Further, the virus may continue to persist and afflict for years to come, as future course of the disease is linked to certain unknown factors like effects of seasonality on virus transmission and unpredictable nature of immune response to the disease.

The infectivity and pathogenesis The agent and infectivity: The causative agent of Covid-19, SARS-CoV-2 involves Angiotensin-converting enzyme 2 (ACE2) receptors on the host tissues to invade and infect. The analysis of the ACE2-RNA expression pro ile indicates that the ACE2-virus receptor expression is mainly concentrated in type II alveolar cells (AT2) in lungs. Further, it is more widespread in males than females, and the Asian men have a higher ACE2-expressing cell ratio than white and African American subjects [1]. In addition, the virus is able to infect ACE2-bearing cells in other organs, including the gastrointestinal tract, heart and blood vessels, and kidneys. The ACE2-expressing AT2, in addition, also express

Witnessing and de ining the disease: The coronaviruses (CoVs) are positive-stranded RNA viruses with a crown-like appearance due to the presence of large spike glycoproteins on the envelope. There are seven CoVs capable of infecting humans (HCoVs), out of which HCoV-OC43 and HCoV-HKU1 (betaCoVs of the A lineage), and HCoV-229E and HCoV-NL63 (alphaCoVs) were identi ied in the 1960s and responsible for about 5% to 10% cases of common cold and short-term upper respiratory infections, with about 2% of the human population being healthy carriers of a CoV. The remaining three HCoVs belonging to betaCoVs of the B and C lineage, have been discovered only in recent years and include SARS-CoV, MERS-CoV and SARS-CoV-2. The newer HCoVs have caused epidemics with variable clinical severity featuring respiratory and extra-respiratory manifestations with the mortality rates up to 10% or more. The 2019-nCoV, also called SARS-CoV-2, was irst reported in Wuhan, China in December 2019. The disease was later named Coronavirus Disease 2019 (COVID-19) and the virus responsible for it as the COVID-19 virus, respectively, by World Health Organization (WHO) [1]. COVID-19 is an acute respiratory disease caused by novel coronavirus SARS-CoV-2 or 2019-nCoV. Recently, on March 11, 2020, COVID-19 was declared by the WHO as a virus pandemic disease.

Like any other infectious disease, the prognosis of COVID-19 is influenced by infecting agent, the SARS-CoV-2 virus load and the extent of organs affliction and damage. COVID-19 having a propensity for multiorgan involvement carries an adverse prognosis during the clinical course as well as later during the post-recovery period persisting as Long Covid. The direct cytopathic effects of SARS-CoV-2 virus and the erratic and hyper-inflammatory response lead to tissue injury in various organs coupled with physiological dysfunctions and complications. In fact, the multi-system manifestations of COVID-19 are caused by a combination of specific host defence responses with associated inflammatory activity and vascular involvement with coagulopathy and a distinct propensity to develop thromboembolic complications. Simultaneously, comorbidities such as diabetes, hypertension and cardiovascular diseases influence the disease severity and mortality.

The Global Virome: The viruses have a global distribution, phylogenetic diversity, and host specificity. They are obligate intracellular parasites with single- or double-stranded DNA or RNA genomes, and afflict bacteria, plants, animals, and human population. The infecting virus binds to receptor proteins on the host cell surface, followed by internalisation, replication, and cell lysis. Further, trans-species interactions of viruses with bacteria, small eukaryotes and host are linked with various zoonotic viral diseases and disease progression.

The immuno-thrombo-inflammatory disease: COVID-19 is an acute immuno-thrombogenic inflammatory viral disease manifested by dysfunctions related to multiple organs involved in its pathogenesis. Its incidence and prevalence of is related to environmental viability of the virus, various transmission factors associated with the agent and the host, possible modes of transmission, period of infectiousness, and composition and susceptibility of the population. Whereas respiratory route is dominant mode of transmission, transmission through direct contact or fomite transmission do occur.

The global virome: The viruses have a global distribution, phylogenetic diversity and host specificity. They are obligate intracellular parasites with single- or double-stranded DNA or RNA genomes, and afflict bacteria, plants, animals and human population. The viral infection begins when surface proteins bind to receptor proteins on the host cell surface, followed by internalisation, replication and lysis. Further, trans-species interactions of viruses with bacteria, small eukaryotes and host are associated with various zoonotic viral diseases and disease progression. Virome interface and transmission: The cross-species transmission from their natural reservoir, usually mammalian or avian, hosts to infect human-being is a rare probability, but occurs leading to the zoonotic human viral infection. The factors like increased human settlements and encroachments, expanded travel and trade networks, altered wildlife and livestock practices, modernised and mass-farming practices, compromised ecosystems and habitat destruction, and global climate change have impact on the interactions between virome and its hosts and other species and act as drivers of trans-species viral spill-over and human transmission. Zoonotic viral diseases and epidemics: The zoonotic viruses have caused various deadly pandemics in human history. They can be further characterized as either newly emerging or re-emerging infectious diseases, caused by pathogens that historically have infected the same host species, but continue to appear in new locations or in drug-resistant forms, or reappear after apparent control or elimination. The prevalence of zoonoses underlines importance of the animal–human–ecosystem interface in disease transmission. The present COVID-19 infection has certain distinct features which suppress the host immune response and promote the disease potential. Treatment for epidemics like covid-19: It appears that certain nutraceuticals may provide relief in clinical symptoms to patients infected with encapsulated RNA viruses such as influenza and coronavirus. These nutraceuticals appear to reduce the inflammation in the lungs and help to boost type 1 interferon response to these viral infections. The human intestinal microbiota acting in tandem with the host’s defence and immune system, is vital for homeostasis and preservation of health. The integrity and balanced activity of the gut microbes is responsible for the protection from disease states including viral infections. Certain probiotics may help in improving the sensitivity and effectivity of immune system against viral infections. Currently, antiviral therapy is available only for a limited number of zoonotic viral infections. Because viruses are intracellular parasites, antiviral drugs are not able to deactivate or destroy the virus but can reduce the viral load by inhibiting replication and facilitating the host’s innate immune mechanisms to neutralize the virus. Conclusion: Lessons from recent viral epidemics - Considering that certain nutraceuticals have demonstrated antiviral effects in both clinical and animal studies, further studies are required to establish their therapeutic efficacy. The components of nutraceuticals such as luteolin, apigenin, quercetin and chlorogenic acid may be useful for developing a combo-therapy. The use of probiotics to enhance immunity and immune response against viral infections is a novel possibility. The available antiviral therapy is inefficient in deactivating or destroying the infecting viruses, may help in reducing the viral load by inhibiting replication. The novel efficient antiviral agents are being explored.