SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic perturbations post recovery, 2022, Frere et al

[SNT Gatchaman]

SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic perturbations post recovery
Justin J. Frere, Randal A. Serafini, Kerri D. Pryce, Marianna Zazhytska, Kohei Oishi, Ilona Golynker, Maryline Panis, Jeffrey Zimering, Shu Horiuchi, Daisy A. Hoagland, Rasmus Møller, Anne Ruiz, Albana Kodra, Jonathan B. Overdevest, Peter D. Canoll, Alain C. Borczuk, Vasuretha Chandar, Yaron Bram, Robert Schwartz, Stavros Lomvardas, Venetia Zachariou, Benjamin R. tenOever

The host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in prolonged pathologies collectively referred to as post-acute sequalae of COVID-19 (PASC) or long COVID.

To better understand the mechanism underlying long COVID biology, we compared the short- and long-term systemic responses in the golden hamster following either SARS-CoV-2 or influenza A virus (IAV) infection.

Results demonstrated that SARS-CoV-2 exceeded IAV in its capacity to cause permanent injury to the lung and kidney and uniquely impacted the olfactory bulb (OB) and epithelium (OE). Despite a lack of detectable infectious virus, the OB and OE demonstrated myeloid and T cell activation, proinflammatory cytokine production, and an interferon response that correlated with behavioral changes extending a month post viral clearance.

These sustained transcriptional changes could also be corroborated from tissue isolated from individuals who recovered from COVID-19. These data highlight a molecular mechanism for persistent COVID-19 symptomology and provide a small animal model to explore future therapeutics.

Link | PDF

 

[SNT Gatchaman]

They used ancestral SARS-CoV-2 so may not be as applicable to newer variants. They compared to influenza A (IAV). The paper suggests that they potentially have an animal model of Long Covid, albeit with limitations against corroboration with humans due to inability to biopsy CNS in patients with mild-moderate disease who don't succumb in the relevant timeframe.

In contrast to the striatum, the thalamus displays a differentially regulated response to SARS-CoV-2 and IAV infection, showing a hypoexcitable versus a hyperexcitable state, respectively. The hypoexcitable state induced by SARS-CoV-2 in the hamster model also show many similarities to clinical reports concerning cognitive deficits and dysexecutive syndrome amongst patients with COVID-19.

These data suggest that thalamic dysregulation may contribute to cognitive disruption, potentially in the form of altered intra-thalamic function or functional connectivity with key brain regions that drive emotion, motivation, cognition, sleep, pain, wakefulness, and motor activity. Altered thalamic function and structure has also been previously associated with cognitive deficits in conditions such as multiple sclerosis, traumatic brain injury, and Alzheimer’s disease.

Thalamic dysfunction may also underlie neurological conditions that have been observed in patients with long COVID including chronic pain, headache, myalgias, seizures, sleep, and affective disorders.

Taken together, our peripheral organ and central nervous system findings identify transcriptional and histologic signatures caused by SARS-CoV-2 infection that may induce a variety of somatosensory, affective, and cognitive impairments that persist well past the time of original infection. Given the systemic scope of these findings, we hypothesize that they elucidate a molecular basis of much of the heterogeneous symptomology that makes up long COVID.

 

[Hutan]

This is an interesting paper, with a lot of analyses. But the study on anxiety/mood changes didn't seem very good.

To determine whether prolonged olfactory bulb inflammation was correlated with altered metrics on assays that assess affective behaviors, mock-, IAV-, and SARS-CoV-2- treated hamsters were subjected to a marble burying assay at 26dpi (Fig. 6D). When hamsters were subjected to this assay, an established metric for assessing rodent repetitive and anxiety-like behaviors (64), SARS-CoV-2-infected animals demonstrated a reduction in burying activity compared to the mock, which performed comparably to the IAV-infected group (Fig. 6D). Behavioral tests such as these are believed to reflect a sign of elevated compulsiveness or anxiety-like behaviors (65). Given this evidence, this behavior suggests that SARS-CoV-2 induces behavioral changes in hamsters.

So, they have this test, supposedly for 'elevated compulsiveness or anxiety-like behaviours' - the number of marbles at least 60% buried by each hamster at 26 days after infection. Clearly, I'm no expert on the behaviour of hamsters, but not burying marbles doesn't sound like 'elevated compulsiveness'. Indeed this study:
Pharmacological evaluation of the adequacy of marble burying as an animal model of compulsion and/or anxiety
concluded

The inability of pramipexole and methyl β-carboline-3-carboxylate to increase marble burying questions the validity of this assay as an adequate animal model of compulsive and/or anxiety behavior.

Furthermore, the literature suggests an increase in marble-burying behaviour is regarded as a sign of increased OCD-ness; diazepam (valium) decreases marble-burying behaviour. The study that is the subject of this thread reports that the previously infected hamsters buried less marbles. Therefore, one interpretation is that they actually became less anxious.


The text claims that the marble-burying study is evidence of behavioural changes caused by the SARS-CoV-2 infection.

But, look at the chart:

All infection groups were assessed for behavior at 26dpi using the marble burying assay, a test classically utilized to measure repetitive, obsessive-compulsive, and anxiety-like behavior in rodents. The number of marbles that were greater than 60% buried were counted and graphed for each hamster. P-values plotted above the graph were calculated for pairwise comparisons using an ordinary one-way ANOVA with Fisher’s Least Significant Difference test. Outliers were corrected for using iterative Grubb’s test. n=1 sample was removed from the SARS-CoV-2 group (with outlier removed: n=14 Mock-infected, n=14 IAV-infected, and n=13 SARS-CoV-2-infected hamsters). Error bars indicate standard error mean.

The differences are not statistically significant. Furthermore, the text under the chart says that they removed an outlier from the SARS-CoV-2 group. But they seem to have kept in two outliers in the mock infection group. So, it really doesn't matter whether the marble-burying test is useful or not. The results of this study do not suggest a difference in marble-burying behaviour, certainly not beyond what you might expect in animals recovering from any infection.

The problem partly originates in the really sloppy epidemiological studies of Long Covid that claim to find increased anxiety as an intrinsic part of the post-acute Covid-19 syndrome. For example, this study's abstract says:

However, a growing body of evidence suggests that, in a subset of individuals, SARS-CoV-2 infection results in prolonged complications including shortness of breath, persistent fevers, fatigue, depression, anxiety, and a state of chronic impairment of memory and concentration known colloquially as “brain fog”. The direct cause of these impairments, known collectively as “long COVID” or post-acute sequalae of COVID-19 (PASC), is currently unknown (32, 33).

But, when we look at the various studies reporting increased anxiety in humans, we find very little to support this idea. And yet, the idea prevails. And although this study found no evidence to support increased anxiety in post-infected animals, and arguably a slight trend to suggest the opposite, the authors have not said that. And so, this idea of increased anxiety (beyond what is an entirely normal response to having an illness that isn't going away and that prevents you from earning a living and doing much of what you love and that there is no cure for) continues.