A study on the basic biology of the long coronavirus

In a recent article published in Translational Medicine Sciences In the journal, researchers analyze the unique prolonged effects of SARS-CoV-2 infection in humans and hamsters after recovery.

​​​​​​The study: SARS-CoV-2 infection in hamsters and humans results in unique and permanent systemic disturbances after recovery. Image Credit: Donkeyworx / Shutterstock

background

SARS-CoV-2 is a respiratory nucleic acid virus (RNA), initially detected in late 2019. SARS-CoV-2 infection has a large number of clinical phenotypes that include a more severe asymptomatic disease, known as 2019-CoV disease. (COVID-19).

COVID-19 causes a mild, flu-like illness in most healthy and young people, with symptoms such as restricted respiratory congestion, muscle aches, fever, loss of smell, and headache. On the other hand, it can cause multiorgan complications, severe respiratory distress, and death in the elderly, especially those with comorbidities and males. It is also hypothesized that SARS-CoV-2 infection inhibits the translation and transcription mechanisms of the host to increase replication, regardless of underlying health or age.

Although the extent of SARS-CoV-2 infection in distant tissues is unknown, severe inflammation remains consistent. According to the information now available, the molecular underpinnings of severe COVID-19 result from damage from the virus and subsequent systemic interaction. The host response to SARS-CoV-2 infection can lead to long-term diseases collectively called COVID-19 or post-acute sequelae of COVID-19 (PASC).

about studying

In this study, scientists chose golden hamsters as a model system to better explain the long-term effects of SARS-CoV-2 infection. The current studies showed that the hamster model closely appears in the biology of SARS-CoV-2 infection without the need for adaptation to SARS-CoV-2 and the tendency to severe emphysema and a morphology similar to that seen in humans.

The team studied the host’s response to SARS-CoV-2 and compared their results with previous influenza A virus (IAV) infections. They investigated long- and short-term systemic responses in golden hamsters after IAV and SARS-CoV-2 infection to understand the mechanism underlying the long biology of COVID.

The researchers adopted SARS-CoV-2 and IAV vaccination doses based on previous investigations to achieve equivalent viral load and kinetics across these two experimental models. In addition, they analyzed lung, heart and kidney cross-sections in hamsters three days after infection using several histological methods to compare SARS-CoV-2-induced pathology versus IAV.

The scientists matched lung RNA-seq analyzes of SARS-CoV-2-infected hamsters with published data from the lungs of deceased COVID-19 patients who still had significant viral loads at death to confirm clinical data for SARS-CoV-2 severe hamster data validity. Moreover, 31 days after SARS-CoV-2 or IAV infection, they evaluated the heart, lung and kidney by histological studies to detect long-term organ damage regardless of transcriptional response. Because COVID for a long time can cause neurological and psychiatric symptoms, the authors examined the effects on the nervous system of SARS-CoV-2 infection.

Given the unique extended duration of the proinflammatory response in the olfactory bulb (OB) to SARS-CoV-2, the researchers analyzed the genes that drive this transcription program. They also investigated whether the olfactory epithelium (OE) had this inflammatory signature. In hamsters infected with SARS-CoV-2 over four weeks after infection, the team evaluated the functional ramifications of chronic neurological changes, such as prolonged OB and OE inflammation. Finally, the researchers used RNA-seq on postmortem OB and OE tissues to determine whether the results could be extrapolated to features of the human disease.

RESULTS AND CONCLUSIONS

The results of the study showed that hamsters infected with IAV and SARS-CoV-2 show a host response similar to human biology and expire within two weeks. Longitudinal data showed that both respiratory RNA viruses replicated in golden hamster lungs, with little variation in SARS-CoV-2 clearance, as previously reported.

Delayed SARS-CoV-2 clearance interfered with decreased appetite as hamsters infected with SARS-CoV-2 gained weight significantly slower than animals infected with IAV or phosphate-buffered saline (PBS). A peak SARS-CoV-2 titer, approximately 108 pfu/g, was observed three days after infection and remained stable until the fifth day before fall.

Although both model systems had different rates of virus replication for extended periods after peak viral titers were achieved, no infectious viruses were able to isolate them at day 7. RNA remained detectable using quantitative reverse transcription-based polymerase chain reaction (qRT-PCR).

SARS-CoV-2 outperformed IAV in causing permanent kidney and lung infection and showed a pronounced effect on OE and OB. Despite the absence of an infectious SARS-CoV-2 payload, the OE and OB harbor T cells and myeloid stimulation, inflammatory cytokine release, and interferon response, all associated with behavioral changes that persisted month after virus clearance.

The researchers note that tissues extracted from those infected with the emerging coronavirus (Covid-19) also confirmed these long-term transcriptional changes. The present findings provide a molecular pathway for the persistence of COVID-19 symptoms and envision a small animal model for testing future treatments.

In conclusion, the results of the study revealed that although both SARS-CoV-2 and IAV elicit a systemic antiviral response, only the previous infection resulted in a long-term inflammatory disease that persists after clearing of the primary infection. The researchers believe that this biology may support the origin of PASC in both hamsters and humans because prolonged inflammation is consistent with behavioral impairments.

Journal reference:

  • JJ Frere, RA Serafini, KD Pryce, et al. , SARS-CoV-2 infection in hamsters and humans leads to unique and permanent systemic disturbances after recovery, Sci. Translation. Med. (2022), DOI: 10.1126/scitranslmed.abq3059, https://www.science.org/doi/10.1126/scitranslmed.abq3059

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