Pathophysiologie

Diverse functional autoantibodies in patients with COVID-19

Wang EY, Mao T, Klein J, Dai Y, Huck JD, Jaycox JR, Liu F, Zhou T, Israelow B, Wong P, Coppi A, Lucas C, Silva J, Oh JE, Song E, Perotti ES, Zheng NS, Fischer S, Campbell M, Fournier JB, Wyllie AL, Vogels CBF, Ott IM, Kalinich CC, Petrone ME, Watkins AE; Yale IMPACT Team, Dela Cruz C, Farhadian SF, Schulz WL, Ma S, Grubaugh ND, Ko AI, Iwasaki A, Ring AM. Nature. 2021 Jul;595(7866):283-288. doi: 10.1038/s41586-021-03631-y. Epub 2021 May 19. PMID: 34010947.

Using a high-throughput autoantibody discovery technique (rapid extracellular antigen profiling); 194 individuals with mild or asymptomatic COVID-19 were screened for auto-antibodies at Yale–New Haven Hospital in the USA. Researchers found that patients with COVID-19 exhibit marked increases in autoantibody reactivity as compared to uninfected individuals, and show a high prevalence of autoantibodies against immunomodulatory proteins (including cytokines, chemokines, complement components and cell-surface proteins). These autoantibodies could perturb immune function and impair virological control by inhibiting immunoreceptor signaling and by altering peripheral immune cell composition. The analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics.

Link to study : Diverse functional autoantibodies in patients with COVID-19

Dysregulation of brain and choroid plexus cell types in severe COVID-19 

Yang AC, Kern F, Losada PM, Agam MR, Maat CA, Schmartz GP, Fehlmann T, Stein JA, Schaum N, Lee DP, Calcuttawala K, Vest RT, Berdnik D, Lu N, Hahn O, Gate D, McNerney MW, Channappa D, Cobos I, Ludwig N, Schulz-Schaeffer WJ, Keller A, Wyss-Coray T. Nature. 2021 Jul;595(7868):565-571. doi: 10.1038/s41586-021-03710-0. Epub 2021 Jun 21. Erratum in: Nature. 2021 Oct;598(7882):E4. PMID: 34153974; PMCID: PMC8400927.

This study included 14 control individuals (one with terminal influenza) and 8 patients with COVID-19 at Stanford University, USA. Profiling of 65 309 single nucleus transcriptomes was done from 30 frontal cortex and choroid plexus samples. There were no molecular traces of SARS-CoV-2 in the brain, however researchers observed broad cellular perturbations indicating that barrier cells of the choroid plexus sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. Researchers also discovered that microglia and astrocyte subpopulations associated with COVID-19 shared features with pathological cell states that have previously been reported in human neurodegenerative disease. Across cell types, perturbations associated with COVID-19 overlap with those found in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia and depression.

Link to study: Dysregulation of brain and choroid plexus cell types in severe COVID-19

18F-FDG brain PET hypometabolism in patients with long COVID

Guedj E, Campion JY, Dudouet P, Kaphan E, Bregeon F, Tissot-Dupont H, Guis S, Barthelemy F, Habert P, Ceccaldi M, Million M, Raoult D, Cammilleri S, Eldin C. Eur J Nucl Med Mol Imaging. 2021 Aug;48(9):2823-2833. doi: 10.1007/s00259-021-05215-4. Epub 2021 Jan 26. PMID: 33501506; PMCID: PMC7837643.

Evaluating PET scans from 35 patients with long COVID in Marseille, France compared to 44 healthy subjects controlled for age and sex, researchers using whole-brain voxel-based analysis found that patients with long COVID had bilateral hypometabolism in the bilateral rectal/orbital gyrus, including the olfactory gyrus; the right temporal lobe, including the amygdala and the hippocampus, extending to the right thalamus; the bilateral pons/medulla brainstem; the bilateral cerebellum (p-voxel < 0.001 uncorrected, p-cluster < 0.05 FWE-corrected). These metabolic clusters were highly discriminant to distinguish patients and healthy subjects (100% correct classification). These clusters of hypometabolism were significantly associated with more numerous functional complaints (brainstem and cerebellar clusters), and all associated with the occurrence of certain symptoms (hyposmia/anosmia, memory/cognitive impairment, pain and insomnia) (p < 0.05).  

Link to study: F-FDG brain PET hypometabolism in patients with long COVID

Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection 

Phetsouphanh C, Darley DR, Wilson DB, Howe A, Munier CML, Patel SK, Juno JA, Burrell LM, Kent SJ, Dore GJ, Kelleher AD, Matthews GV. Nat Immunol. 2022 Jan 13. doi: 10.1038/s41590-021-01113-x. Epub ahead of print. PMID: 35027728.

This study evaluated individuals with long COVID in Sydney, Australia compared to age- and gender- matched recovered individuals without long COVID, unexposed donors and individuals infected with other coronaviruses. Patients with long COVID had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1) that remained persistently high at 8 months after infection. Combinations of the inflammatory mediators IFN-β, PTX3, IFN-γ, IFN-λ2/3 and IL-6 were associated with long COVID with 78.5–81.6% accuracy.  

Link to study: Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection

Immunoglobulin signature predicts risk of post-acute COVID-19 syndrome

Cervia C, Zurbuchen Y, Taeschler P, Ballouz T, Menges D, Hasler S, Adamo S, Raeber ME, Bächli E, Rudiger A, Stüssi-Helbling M, Huber LC, Nilsson J, Held U, Puhan MA, Boyman O. Nat Commun. 2022 Jan 25;13(1):446. doi: 10.1038/s41467-021-27797-1. PMID: 35078982.

Comparing 123 patients with COVID-19 to 35 healthy controls in Switzerland, researchers found an association between levels of IgM and IgG3, combined with age, asthma and five symptoms (fever, fatigue, cough, dyspnea and gastrointestinal symptoms) during the acute phase of the infection and the risk of post-COVID, independently of the time-point of blood sampling. This was validated with an independent cohort of 395 individuals with COVID-19.

Link to study:  Immunoglobulin signature predicts risk of post-acute COVID-19 syndrome

Antibodies in SARS-CoV-2 Infection and Vaccination 

Murphy WJ, Longo DL. A. Possible Role for Anti-idiotype N Engl J Med. 2022 Jan 27;386(4):394-396. doi: 10.1056/NEJMcibr2113694. Epub 2021 Nov 24. PMID: 34818473.

Authors discuss the role of the spike (S) protein and its critical use of the angiotensin-converting–enzyme 2 (ACE2) receptor to gain entry into the cell and suggest a possible role for Anti-idiotype antibodies in SARS-CoV-2 infection and vaccination. Studies should further characterize all antibody and T-cell responses to the virus and the vaccines, including Ab2 responses and Ab1 maintenance and efficacy.

Link to study: Possible Role for Anti-idiotype Antibodies in SARS-CoV-2 Infection and Vaccination

Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae

Su, Y., Yuan, D., Chen, D.G., Ng, R.H., Wang, K., Choi, J., Li, S., Hong, S., Zhang, R., Xie, J., Kornilov, S.A., Scherler, K., Pavlovitch-Bedzyk, A.J., Dong, S., Lausted, C., Lee, I., Fallen, S., Dai, C.L., Baloni, P., Smith, B., Duvvuri, V.R., Anderson, K.G., Li, J., Yang, F., Duncombe, C.J., McCulloch, D.J., Rostomily, C., Troisch, P., Zhou, J., Mackay, S., DeGottardi, Q., May, D.H, Taniguchi, R., Gittelman, R.M, Klinger, M., Snyder, T.M, Roper, R., Wojciechowska, G., Murray, K., Edmark, R., Evans, S., Jones, L., Zhou, Y., Rowen, L., Liu, R., Chour, W., Algren, H.A, Berrington, W.R., Wallick, J.A., Cochran, R.A., Micikas, M.E., the ISB-Swedish COVID19 Biobanking Unit, Terri Wrin, Petropoulos, C.J., Cole, H.R., Fischer, T.D., Wei, W., Hoon, D.S.B., Price, N.D., Subramanian, N., Hill, J.A, Hadlock, J., Magis, A.T., Ribas, A., Lanier, L.L., Boyd, S.D. Bluestone, J.A., Chu, H., Hood, L., Gottardo, R., Greenberg, P.D., Davis, M.M., Goldman, J.D., Heath, J.R. Cell (2022), doi: https://doi.org/10.1016/j.cell.2022.01.014.

Researchers from Seattle, Washington, USA executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, and patient-reported symptoms. Four post-COVID risk factors were identified, at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal post-COVID, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four 10 endotypes exhibiting divergent acute severity and post-COVID. Immunological associations between post-COVID factors diminished over time leading to distinct convalescent immune states. 

Link to study : Multiple Early Factors Anticipate Post-Acute COVID-19 Sequelae

Human small intestinal infection by SARS-CoV-2 is characterized by a mucosal infiltration with activated CD8 + T cells 

Lehmann M, Allers K, Heldt C, Meinhardt J, Schmidt F, Rodriguez-Sillke Y, Kunkel D, Schumann M, Böttcher C, Stahl-Hennig C, Elezkurtaj S, Bojarski C, Radbruch H, Corman VM, Schneider T, Loddenkemper C, Moos V, Weidinger C, Kühl AA, Siegmund B. Mucosal Immunol. 2021 Nov;14(6):1381-1392. doi: 10.1038/s41385-021-00437-z. Epub 2021 Aug 21. PMID: 34420043; PMCID: PMC8379580.

Researchers analyzed biopsies of the small intestine from SARS-CoV-2 infected individuals at Charité-Universitätsmedizin, Berlin, and detected SARS-CoV-2 RNA and nucleocapsid protein using qRT-PCR and immunohistochemistry in duodenal mucosa. Researchers also identified histomorphological changes of the epithelium, which were characterized by an accumulation of activated intraepithelial CD8+ T cells as well as epithelial apoptosis and subsequent regenerative proliferation in the small intestine of COVID-19 patients.

Link to study: Human small intestinal infection by SARS-CoV-2 is characterized by a mucosal infiltration with activated CD8 + T cells

Persistent SARS-CoV-2 Nucleocapsid Protein Presence in the Intestinal Epithelium of a Pediatric Patient 3 Months After Acute Infection 

Arostegui D, Catro K, Schwarz S, Vaidy K, RABINOWITZ s, Wallach T. JPGN Reports: February 2022 - Volume 3 - Issue 1 - p e152 doi: 10.1097/PG9.0000000000000152.

This case report describes the case of an 11-year-old female at the Children’s Hospital at Downstate, New York, USA, with chronic abdominal pain following a PCR-positive COVID infection, with histopathology of biopsied colonic tissue 3 months after the infection showing dense lymphocytic infiltrates, and SARS-CoV-2 evidence identified on immunohistochemical staining. 

Link to study : Persistent SARS-CoV-2 Nucleocapsid Protein Presence in the Intestinal Epithelium of a Pediatric Patient 3 Months After Acute Infection