Study on the underlying biology of long COVID

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

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

Background

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

COVID-19 causes a mild flu-like disease in most healthy and young people, with symptoms such as restricted respiratory tract congestion, myalgia, fever, anosmia, and headache. On the other hand, it can cause multi-organ complications, severe respiratory distress, and death in old-aged, especially those with co-morbidities and males. SARS-CoV-2 infection is also hypothesized to inhibit host translational and transcriptional mechanisms to increase replication, regardless of underlying health or age.

Although the extent to which distal tissues are infected in a SARS-CoV-2 infection is unknown, extensive inflammation is constant. According to the information now available, the molecular foundations of acute COVID-19 are the resultant of the damage induced by the virus and the subsequent systemic reaction. The host response to SARS-CoV-2 infection can lead to long-lasting diseases collectively termed as long COVID or post-acute sequelae of COVID-19 (PASC). 

About the study

In the present study, the scientists chose the golden hamster as the model system to better explain the long-term impacts of SARS-CoV-2 infection. Existing studies showed that the hamster model closely phenocopies SARS-CoV-2 infection biology without the requirement for SARS-CoV-2 adaption and a propensity for severe lung tropism and morphology similar to those seen in humans. 

The team studied the host response to SARS-CoV-2 and compared their findings to a previous influenza A virus (IAV) pandemic virus infection. They investigated the long- and short-term systemic responses in the golden hamster following IAV and SARS-CoV-2 infection to better comprehend the mechanism underpinning the biology of long COVID.

The researchers adopted past investigation-based SARS-CoV-2 and IAV inoculation dosages to achieve equivalent viral load and kinetics across these two experimental models. In addition, they analyzed cross-sections of the lung, heart, and kidney in hamsters three days after infection employing several histological methods to compare the pathology caused by SARS-CoV-2 against IAV.

The scientists matched the lung RNA-seq analyses of SARS-CoV-2-infected hamsters to published data from the lungs of COVID-19 deceased patients who still had significant viral loads at death to confirm the SARS-CoV-2 acute hamster data's clinical validity. Further, 31 days after SARS-CoV-2 or IAV infection, they assessed the heart, lung, and kidney by histological studies to detect long-lasting organ damage irrespective of the 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.

Considering 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 transcriptional program. They also investigated if olfactory epithelium (OE) had this proinflammatory signature. In SARS-CoV-2-infected hamsters over four weeks post-infection, the team evaluated the functional repercussions of chronic neuronal alterations, like prolonged OB and OE inflammation. Lastly, the researchers used RNA-seq on post-mortem OB and OE tissue to determine if 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 resolve within two weeks. Longitudinal data showed that both respiratory RNA viruses multiplied in the golden hamster's lungs, with just a minor variance in SARS-CoV-2 clearance, as previously reported.

The delayed SARS-CoV-2 clearance overlapped with a reduced appetite as the SARS-CoV-2-infected hamsters gained weight notably slower than IAV-infected or phosphate-buffered saline (PBS)-treated animals. Peak SARS-CoV-2 titers, roughly 108 pfu/g, were observed three days after infection and remained stable until day five before dropping. 

Although both model systems had different rates of prolonged virus replication after achieving peak viral titers, no infectious viruses were able to isolate on day 7. By contrast, influenza nucleoprotein (NP) RNA and SARS-CoV-2 sub-genomic 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 injury and exhibited a distinct effect on the OE and OB. Despite the absence of the infectious SARS-CoV-2 load, the OE and OB harbored T cell and myeloid stimulation, proinflammatory cytokine release, and interferon response, all linked to behavioral alterations that lasted a month after viral clearance. 

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

To conclude, the study findings reveal that although both SARS-CoV-2 and IAV cause a systemic antiviral response, just the former infection led to a long-term inflammatory pathology that persists after the primary infection has been cleared. The investigators believe that this biology might underpin the origin of PASC in both hamsters and humans because prolonged inflammation corresponds with behavioral impairments.

Journal reference:
  • J. J. Frere, R. A. Serafini, K. D. Pryce, et al., SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic perturbations post-recovery, Sci. Transl. Med. (2022),  DOI: 10.1126/scitranslmed.abq3059, https://www.science.org/doi/10.1126/scitranslmed.abq3059
Shanet Susan Alex

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Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.

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