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

Study on the underlying biology of long COVID

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

​​​​​​​Study: SARS-CoV-2 infection in hamsters and humans leads to long-lasting and unique systemic disruptions after recovery. Image Credit: Donkeyworx / Shutterstock

Background

SARS-CoV-2 is a ribonucleic acid (RNA) respiratory virus, initially discovered in late 2019. SARS-CoV-2 infection has a plethora of clinical phenotypes including asymptomatic and more severe disease, commonly referred to as CoV disease 2019 (COVID-19).

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

Although the extent to which distal tissues are infected during SARS-CoV-2 infection is unknown, extensive inflammation is consistent. According to the information now available, the molecular basis of acute COVID-19 results from the damage induced by the virus and the resulting systemic reaction. The host response to SARS-CoV-2 infection can lead to long-lasting illnesses collectively referred to as long COVID or post-acute sequelae of COVID-19 (PASC).

About the study

In the present study, scientists chose the golden hamster as a model system to better explain the long-term impacts of SARS-CoV-2 infection. Existing studies have shown that the hamster model closely copies the biology of SARS-CoV-2 infection without requiring adaptation to SARS-CoV-2 and a propensity for severe lung tropism and morphology similar to those observed in humans.

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

Researchers adopted investigation-based SARS-CoV-2 and IAV inoculation doses to achieve equivalent doses viral load and kinetics through these two experimental models. Additionally, they analyzed cross-sections of the lung, heart, and kidney in hamsters three days post-infection using multiple histological methods to compare the pathology caused by SARS-CoV-2 to IAV.

Scientists matched lung RNA-seq analyzes from SARS-CoV-2 infected hamsters to published data from the lungs of deceased COVID-19 patients who still had significant viral loads at death to confirm the data. SARS-CoV-2 acute hamster clinics. validity. In addition, 31 days after infection with SARS-CoV-2 or IAV, they evaluated the heart, lungs and kidneys by histological studies to detect long-lasting organ damage, regardless of transcriptional response. Since long COVID can cause neuropsychiatric and neurological symptoms, the authors examined the effects on the nervous system resulting from SARS-CoV-2 infection.

Given the uniquely prolonged duration of the pro-inflammatory response in the olfactory bulb (OB) to SARS-CoV-2, researchers analyzed the genes that drive this transcription program. They also investigated whether the olfactory epithelium (OE) had this pro-inflammatory signature. In hamsters infected with SARS-CoV-2 for four weeks after infection, the team assessed the functional repercussions of chronic neuronal alterations, such as prolonged inflammation of the OB and OE. Finally, the researchers used RNA-seq on OB and OE tissues post-mortem to determine if the results could be extrapolated to human disease characteristics.

Results and conclusions

Study results showed that hamsters infected with IAV and SARS-CoV-2 exhibit a host response similar to human biology and resolve within two weeks. Longitudinal data showed that both RNA respiratory viruses multiplied in golden hamster lungs, with just a minor discrepancy in SARS-CoV-2 clearance, as previously reported.

Delayed SARS-CoV-2 clearance overlapped with reduced appetite as SARS-CoV-2 infected hamsters gained significantly slower weight than infected phosphate buffered saline (PBS) treated animals by IAV. Maximum SARS-CoV-2 titers, approximately 108 pfu/g, were observed three days after infection and remained stable until the fifth day before falling.

Although the two model systems had different rates of sustained viral replication after reaching peak viral titers, no infectious virus was able to isolate by day 7. In contrast, influenza nucleoprotein (NP) RNA and the 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 kidney and lung damage and showed a distinct effect on OE and OB. Despite the absence of the SARS-CoV-2 infectious load, OE and OB harbored T-cell and myeloid stimulation, pro-inflammatory cytokine release, and response to interferon, all related to behavioral alterations that lasted one month after viral clearance.

The researchers noted that tissue extracted from COVID-19 convalescent individuals also confirmed these long-term transcriptional alterations. The current findings offer a molecular pathway for the persistence of COVID-19 symptoms and outline a small animal paradigm for testing future therapeutics.

In conclusion, the study results reveal that although both SARS-CoV-2 and IAV elicit a systemic antiviral response, only the first infection led to long-term inflammatory pathology that persists after elimination of the virus. primary infection. The researchers believe that this biology may underlie the origin of PASC in hamsters and humans, as prolonged inflammation correlates with behavioral disturbances.

Journal reference:

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