Study: SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic perturbations post recovery. Image Credit: Donkeyworx / Shutterstock

Exploring the underlying biology of long-term COVID

In a recent article published in the Science Translational Medicine magazine, researchers analyzed long-term and unique implications of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans and hamsters after recovery.

Study: SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic disruptions after recovery† ​​​​​​​Image Credit: Donkeyworx / Shutterstock

Background

SARS-CoV-2 is a respiratory ribonucleic acid (RNA) virus, first discovered in late 2019. SARS-CoV-2 infection possesses a plethora of clinical phenotypes that include asymptomatic and more severe disease, commonly known as CoV disease 2019 (COVID-19 ).

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

Although the extent to which distal tissues are infected in SARS-CoV-2 infection is unknown, there is constant extensive inflammation. According to the information now available, the molecular foundations of acute COVID-19 are the result of the damage caused by the virus and the subsequent systemic response. The host’s response to SARS-CoV-2 infection can lead to long-term illnesses collectively referred to as long-term COVID or post-acute consequences of COVID-19 (PASC).

About the study

In the current study, the scientists chose the golden hamster as a model system to better explain the long-term effects of SARS-CoV-2 infection. Existing studies have shown that the hamster model accurately phenocopies SARS-CoV-2 infection biology without the need for SARS-CoV-2 adaptation and a tendency for severe lung tropism and morphology similar to that in humans.

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

The researchers have historically adopted research-based SARS-CoV-2 and IAV inoculation doses to achieve equivalent viral load and kinetics across these two experimental models. In addition, they analyzed cross-sections of the lungs, heart and kidneys in hamsters three days after infection using different histological methods to compare the pathology caused by SARS-CoV-2 with IAV.

The scientists linked the 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 provide the clinical clinical data from the confirm acute SARS-CoV-2 hamster data. Validity. Further, 31 days after SARS-CoV-2 or IAV infection, they assessed the heart, lungs, and kidneys by histological examinations to detect long-term organ damage regardless of the transcriptional response. Because COVID has long been able to cause neuropsychiatric and neurological symptoms, the authors examined the effects on the nervous system due to SARS-CoV-2 infection.

Given the unique prolonged 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 examined whether olfactory epithelium (OE) had this pro-inflammatory signature. In SARS-CoV-2 infected hamsters for four weeks after infection, the team evaluated the functional consequences of chronic neuronal changes, such as long-term OB and OE inflammation. Finally, the researchers used RNA-seq on post-mortem OB and OE tissue to determine whether the results could be extrapolated to features of human disease.

Results and conclusions

The study results showed that IAV and SARS-CoV-2 infected hamsters exhibit a host response similar to human biology and disappear within two weeks. Longitudinal data showed that both respiratory RNA viruses multiplied in the lungs of the golden hamster, with only a small deviation in the clearance of SARS-CoV-2, as previously reported.

The delayed clearance of SARS-CoV-2 overlapped with a decreased appetite, as the SARS-CoV-2 infected hamsters gained weight significantly more slowly than IAV-infected or phosphate-buffered saline (PBS) treated animals. Peak SARS-CoV-2 titers, approximately 108 pfu/g, were observed three days post-infection and remained stable through day five before declining.

Although both model systems had different rates of extended virus replication after reaching maximal viral titers, no infectious viruses could be isolated by day 7. In contrast, influenza nucleoprotein (NP) RNA and SARS-CoV-2 subgenomic nucleocapsid (sgN) RNA remained detectable using quantitative reverse transcription-based polymerase chain reaction (qRT-PCR).

SARS-CoV-2 outperformed IAV in causing permanent renal and lung injury and showed a marked effect on OE and OB. Despite the absence of the infectious SARS-CoV-2 cargo, the OE and OB . harbored T-cell and myeloid stimulation, pro-inflammatory cytokine release and interferon response, all linked to behavioral changes that persisted for one month after viral clearance.

The researchers noted that tissue extracted from the recovering individuals from COVID-19 also confirmed these long-term transcriptional changes. The current findings provide a molecular pathway for the persistence of COVID-19 symptoms and demonstrate a small animal paradigm for testing future therapies.

In conclusion, the study results show that although both SARS-CoV-2 and IAV elicit a systemic antiviral response, only the first infection led to a long-lasting inflammatory pathology that persists after the primary infection has resolved. The researchers believe that this biology could support the origin of PASC in both hamsters and humans, as long-term inflammation is consistent with behavioral disturbances.

Reference magazine:

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