Understanding the outcomes of COVID-19 – does the current model of an acute respiratory infection really fit?

Abstract

Although coronavirus disease 2019 (COVID-19) is regarded as an acute, resolving infection followed by the development of protective immunity, recent systematic literature review documents evidence for often highly prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory and faecal samples, periodic recurrence of PCR positivity in a substantial proportion of individuals and increasingly documented instances of reinfection associated with a lack of protective immunity. This pattern of infection is quite distinct from the acute/resolving nature of other human pathogenic respiratory viruses, such as influenza A virus and respiratory syncytial virus. Prolonged shedding of SARS-CoV-2 furthermore occurs irrespective of disease severity or development of virus-neutralizing antibodies. SARS-CoV-2 possesses an intensely structured RNA genome, an attribute shared with other human and veterinary coronaviruses and with other mammalian RNA viruses such as hepatitis C virus. These are capable of long-term persistence, possibly through poorly understood RNA structure-mediated effects on innate and adaptive host immune responses. The assumption that resolution of COVID-19 and the appearance of anti-SARS-CoV-2 IgG antibodies represents virus clearance and protection from reinfection, implicit for example in the susceptible–infected–recovered (SIR) model used for epidemic prediction, should be rigorously re-evaluated.

Absolute quantitation of individual SARS-CoV-2 RNA molecules: a new paradigm for infection dynamics and variant differences

“…We found that SARS-CoV-2 gRNA persisted in the presence of RDV, suggesting a long halflife that may reflect the high secondary structure of the RNA genome that could render it refractory to the action of nucleases (Simmonds et al, 2021). smFISH revealed complex dynamics of gRNA and sgRNA expression that resulted in a rapid expansion of sgRNA (peaking at 8hpi), followed by a shift towards the production of gRNA (24 hpi), results that were confirmed by RNAseq.…”

What we know about covid-19 reinfection so far

“…Research conducted at the Nuffield Department of Medicine at the University of Oxford purports that many of the cases of reinfection may actually be reactivation 5. Mossong points out that coronaviruses give long infections and their large genomic structures could cause them to remain in the body at low enough levels to remain undetected but ready to strike once more.…”

Potential Achilles heels of SARS-CoV-2 are best displayed by the base order-dependent component of RNA folding energy

“…This may be because the importance of removing redundant information and analyzing solely the contribution of base order to folding energy, was not fully appreciated. Even those who have employed the same technology have expressed puzzlement at the "biological purpose" of so much "pervasive RNA secondary structure in the genomes of SARS-CoV-2 and other coronaviruses" (Simmonds 2020a) and regret the "poorly understood RNA structure-mediated effects on innate and adaptive host immune responses" (Simmonds et al, 2020). Thus, we have here repeated and expanded on past clarifications (Forsdyke 2007a;Xu et al, 2007; of the conceptual basis of a technology that has contributed to the understanding of a many biological problems other than viral infections (Forsdyke 2016).…”