Survey of Anti-Pathogen Antibody Levels in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Infectious pathogens are implicated in the etiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) because of the occurrence of outbreaks of the disease. While a number of different infectious agents have been associated with the onset of ME/CFS, the identity of a specific organism has been difficult to determine in individual cases. The aim of our study is to survey ME/CFS subjects for evidence of an infectious trigger and/or evidence of immune dysregulation via serological testing of plasma samples for antibodies to 122 different pathogen antigens.
Immune profiles were compared to age-, sex-, and BMI-matched controls to provide a basis for comparison. Antibody levels to individual antigens surveyed in this study do not implicate any one of the pathogens in ME/CFS, nor do they rule out common pathogens that frequently infect the US population. However, our results revealed sex-based differences in steady-state humoral immunity, both within the ME/CFS cohort and when compared to trends seen in the healthy control cohort.
Source: O’Neal AJ, Glass KA, Emig CJ, Vitug AA, Henry SJ, Shungu DC, Mao X, Levine SM, Hanson MR. Survey of Anti-Pathogen Antibody Levels in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Proteomes. 2022; 10(2):21. https://doi.org/10.3390/proteomes10020021 https://www.mdpi.com/2227-7382/10/2/21/htm (Full text)

SARS-CoV-2 infection and persistence throughout the human body and brain

Abstract:

COVID-19 is known to cause multi-organ dysfunction1-3 in acute infection, with prolonged symptoms experienced by some patients, termed Post-Acute Sequelae of SARS-CoV-2 (PASC)4-5. However, the burden of infection outside the respiratory tract and time to viral clearance is not well characterized, particularly in the brain3,6-14.
We performed complete autopsies on 44 patients with COVID-19 to map and quantify SARS-CoV-2 distribution, replication, and cell-type specificity across the human body, including brain, from acute infection through over seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, even among patients who died with asymptomatic to mild COVID-19, and that virus replication is present in multiple extrapulmonary tissues early in infection.
Further, we detected SARS-CoV-2 RNA in multiple anatomic sites, including regions throughout the brain, for up to 230 days following symptom onset. Despite extensive distribution of SARS-CoV-2 in the body, we observed a paucity of inflammation or direct viral cytopathology outside of the lungs. Our data prove that SARS-CoV-2 causes systemic infection and can persist in the body for months.
Source: Daniel Chertow, Sydney Stein, Sabrina Ramelli et al. SARS-CoV-2 infection and persistence throughout the human body and brain, 20 December 2021, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-1139035/v1] https://www.researchsquare.com/article/rs-1139035/v1 https://www.nature.com/articles/s41586-022-05542-y (Full text)

Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation: a longitudinal observational study

Abstract:

Cognitive impairment and function post-acute mild to moderate COVID-19 are poorly understood. We report findings of 128 prospectively studied SARS-CoV-2 positive patients. Cognition and olfaction were assessed at 2-, 4- and 12-months post-diagnosis. Lung function, physical and mental health were assessed at 2-month post diagnosis. Blood cytokines, neuro-biomarkers, and kynurenine pathway (KP) metabolites were measured at 2-, 4-, 8- and 12-months. Mild to moderate cognitive impairment (demographically corrected) was present in 16%, 23%, and 26%, at 2-, 4- and 12-months post diagnosis, respectively. Overall cognitive performance mildly, but significantly (p<.001) declined. Cognitive impairment was more common in those with anosmia (p=.05), but only at 2 months. KP metabolites quinolinic acid, 3-hydroxyanthranilic acid, and kynurenine were significantly (p<.001) associated with cognitive decline. The KP as a unique biomarker offers a potential therapeutic target for COVID-19-related cognitive impairment.

Source: Lucette A. Cysique, David Jakabek, Sophia G. Bracken, Yasmin Allen-Davidian, Benjamin Heng, Sharron Chow, Mona Dehhaghi, Ananda Staats Pires, David R. Darley, Anthony Byrne, Chansavath Phetsouphanh, Anthony Kelleher, Gregory J. Dore, Gail V. Matthews, Gilles J Guillemin, Bruce J. Brew. Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation: a longitudinal observational study. medRxiv 2022.06.07.22276020; doi: https://doi.org/10.1101/2022.06.07.22276020 https://www.medrxiv.org/content/10.1101/2022.06.07.22276020v1.full-text (Full text)

Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain

Abstract:

The prevalence and severity of many chronic pain syndromes differ across sex, and recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn, direct investigations using rodent and human preclinical pain models have been lacking.

Here, we discovered that in the Freund’s adjuvant in vivo model of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between KCC2-dependent disinhibition and N-methyl-D-aspartate receptor (NMDAR) potentiation within superficial dorsal horn neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator brain-derived neurotrophic factor (BDNF) failed to downregulate inhibitory signalling elements (KCC2 and STEP61) and upregulate excitatory elements (pFyn, GluN2B and pGluN2B) in female rats, resulting in no effect of ex vivo brain-derived neurotrophic factor on synaptic NMDAR responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans.

As in rodents, ex vivo spinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in superficial dorsal horn neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain neuronal phenotype, with BDNF driving a coupling between disinhibition and NMDAR potentiation in adult lamina I neurons following the prepubescent elimination of sex hormones in females. This discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment for pain in both sexes.

Source: Dedek A, Xu J, Lorenzo LÉ, Godin AG, Kandegedara CM, Glavina G, Landrigan JA, Lombroso PJ, De Koninck Y, Tsai EC, Hildebrand ME. Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain. Brain. 2022 Apr 29;145(3):1124-1138. doi: 10.1093/brain/awab408. PMID: 35323848; PMCID: PMC9050559. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9050559/ (Full text)

Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae

Abstract:

The diagnosis and management of post-acute sequelae of COVID-19 (PASC) poses an ongoing medical challenge. Identifying biomarkers associated with PASC would immensely improve the classification of PASC patients and provide the means to evaluate treatment strategies. We analyzed plasma samples collected from a cohort of PASC and COVID-19 patients (n = 63) to quantify circulating viral antigens and inflammatory markers. Strikingly, we detect SARS-CoV-2 spike antigen in a majority of PASC patients up to 12 months post-diagnosis, suggesting the presence of an active persistent SARS-CoV-2 viral reservoir. Furthermore, temporal antigen profiles for many patients show the presence of spike at multiple time points over several months, highlighting the potential utility of the SARS-CoV-2 full spike protein as a biomarker for PASC

Source: Zoe Swank, Yasmeen Senussi, Galit Alter, David R. Walt. Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae. medRxiv 2022.06.14.22276401; doi: https://doi.org/10.1101/2022.06.14.22276401 https://www.medrxiv.org/content/10.1101/2022.06.14.22276401v1 (Full text available as PDF file)

Novel genes and sex differences in COVID-19 severity

Abstract:

Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5×10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3×10-22 and p = 8.1×10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4×10-8).

In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7×10-8) and ARHGAP33 (p = 1.3×10-8), respectively.

The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1×10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE.

We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

Source: Cruz R, Almeida SD, Heredia ML, Quintela I, Ceballos FC, Pita G, Lorenzo-Salazar JM, González-Montelongo R, Gago-Domínguez M, Porras MS, Castaño JAT, Nevado J, Aguado JM, Aguilar C, Aguilera-Albesa S, Almadana V, Almoguera B, Alvarez N, Andreu-Bernabeu Á, Arana-Arri E, Arango C, Arranz MJ, Artiga MJ, Baptista-Rosas RC, Barreda-Sánchez M, Belhassen-Garcia M, Bezerra JF, Bezerra MAC, Boix-Palop L, Brion M, Brugada R, Bustos M, Calderón EJ, Carbonell C, Castano L, Castelao JE, Conde-Vicente R, Cordero-Lorenzana ML, Cortes-Sanchez JL, Corton M, Darnaude MT, De Martino-Rodríguez A, Campo-Pérez V, Bustamante AD, Domínguez-Garrido E, Luchessi AD, Eirós R, Sanabria GME, Fariñas MC, Fernández-Robelo U, Fernández-Rodríguez A, Fernández-Villa T, Gil-Fournier B, Gómez-Arrue J, Álvarez BG, Quirós FGB, González-Peñas J, Gutiérrez-Bautista JF, Herrero MJ, Herrero-Gonzalez A, Jimenez-Sousa MA, Lattig MC, Borja AL, Lopez-Rodriguez R, Mancebo E, Martín-López C, Martín V, Martinez-Nieto O, Martinez-Lopez I, Martinez-Resendez MF, Martinez-Perez Á, Mazzeu JA, Macías EM, Minguez P, Cuerda VM, Silbiger VN, Oliveira SF, Ortega-Paino E, Parellada M, Paz-Artal E, Santos NPC, Pérez-Matute P, Perez P, Pérez-Tomás ME, Perucho T, Pinsach-Abuin ML, Pompa-Mera EN, Porras-Hurtado GL, Pujol A, León SR, Resino S, Fernandes MR, Rodríguez-Ruiz E, Rodriguez-Artalejo F, Rodriguez-Garcia JA, Ruiz-Cabello F, Ruiz-Hornillos J, Ryan P, Soria JM, Souto JC, Tamayo E, Tamayo-Velasco A, Taracido-Fernandez JC, Teper A, Torres-Tobar L, Urioste M, Valencia-Ramos J, Yáñez Z, Zarate R, Nakanishi T, Pigazzini S, Degenhardt F, Butler-Laporte G, Maya-Miles D, Bujanda L, Bouysran Y, Palom A, Ellinghaus D, Martínez-Bueno M, Rolker S, Amitrano S, Roade L, Fava F, Spinner CD, Prati D, Bernardo D, Garcia F, Darcis G, Fernández-Cadenas I, Holter JC, Banales JM, Frithiof R, Duga S, Asselta R, Pereira AC, Romero-Gómez M, Nafría-Jiménez B, Hov JR, Migeotte I, Renieri A, Planas AM, Ludwig KU, Buti M, Rahmouni S, Alarcón-Riquelme ME, Schulte EC, Franke A, Karlsen TH, Valenti L, Zeberg H, Richards B, Ganna A, Boada M, Rojas I, Ruiz A, Sánchez P, Real LM; SCOURGE Cohort Group; HOSTAGE Cohort Group; GRA@CE Cohort Group, Guillen-Navarro E, Ayuso C, González-Neira A, Riancho JA, Rojas-Martinez A, Flores C, Lapunzina P, Carracedo Á. Novel genes and sex differences in COVID-19 severity. Hum Mol Genet. 2022 Jun 16:ddac132. doi: 10.1093/hmg/ddac132. Epub ahead of print. PMID: 35708486.  https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddac132/6607933  (Full text available as PDF file)

Impaired Cardiac Autonomic Control in Women With Fibromyalgia Is Independent of Their Physical Fitness

Abstract:

Background/objective: Evidence has suggested abnormal cardiac autonomic responses to exercise in patients with fibromyalgia (FM). However, it is not clear whether the dysautonomia represents a reduced physical fitness rather directly related to FM pathogenesis. Thus, we aimed to verify the cardiac autonomic responses before, during, and after a maximal incremental exercise in women with FM and whether these hypothesized alterations would be dependent with their physical fitness.

Methods: This is a cross-sectional study with 23 FM women and 17 healthy women. The participants performed a maximal incremental cycling test to determine their maximal workload (Wmax) and were further matched by their Wmax (14 FM patients, Wmax: 128.6 ± 16.2 W; and 14 healthy women, Wmax: 131.9 ± 15.9 W). Beat-to-beat heart rate (HR) was continuously monitored to calculate HR variability indexes at rest, chronotropic reserve during exercise, and HR recovery.

Results: Heart rate variability indexes related to vagal modulation were significantly lower in FM patients than in healthy women (p < 0.05). The chronotropic reserve and the HR recovery at 30, 120, 180, 300, and 600 seconds after exercise were all lower in FM patients compared with those of healthy women (p < 0.05). Similar findings were found when analysis was performed using the matched physical fitness subgroup.

Conclusions: The documented cardiac autonomic abnormalities at rest, during, and after exercise in FM patients persist even when physical fitness status is taken in account. Thus, strategies to attenuate the dysautonomia in FM patients must be considered.

Source: Schamne JC, Ressetti JC, Lima-Silva AE, Okuno NM. Impaired Cardiac Autonomic Control in Women With Fibromyalgia Is Independent of Their Physical Fitness. J Clin Rheumatol. 2021 Sep 1;27(6S):S278-S283. doi: 10.1097/RHU.0000000000001518. PMID: 32826659. https://pubmed.ncbi.nlm.nih.gov/32826659/

Prevalence of fibromyalgia 10 years after infection with Giardia lamblia: a controlled prospective cohort study

Abstract:

Objectives: To investigate whether acute infection with Giardia lamblia is associated with fibromyalgia 10 years after infection and whether fibromyalgia is associated with irritable bowel syndrome (IBS) and chronic fatigue (CF) in this setting.

Methods: A cohort study was established after an outbreak of G. lamblia in Bergen, Norway, 2004. Laboratory-confirmed cases and a matched control group were followed for 10 years. The main outcome was fibromyalgia 10 years after giardiasis, defined by the 2016 revisions of the fibromyalgia diagnostic criteria using the Fibromyalgia Survey Questionnaire (FSQ).

Results: The prevalence of fibromyalgia was 8.6% (49/572) among Giardia exposed compared to 3.1% (21/673) in controls (p<0.001). Unadjusted odds for having fibromyalgia was higher for Giardia exposed compared to controls (odds ratio (OR): 2.91, 95% confidence interval (CI): 1.72, 4.91), but adjusted for IBS and CF it was not (OR: 1.05, 95% CI: 0.57, 1.95). Among participants without CF the odds for fibromyalgia was 6.27 times higher for participants with IBS than those without (95% CI: 3.31, 11.91) regardless of exposure. Among participants without IBS the odds for fibromyalgia was 4.80 times higher for those with CF than those without (95% CI: 2.75, 8.37).

Conclusions: We found a higher prevalence of fibromyalgia among Giardia exposed compared to controls 10 years after the acute infection. Fibromyalgia was strongly associated with IBS and CF, and the difference between the exposed and controls can be attributed to the high prevalence of IBS and CF among the Giardia exposed. Notably, this study was not designed to establish causality between Giardia exposure and the outcomes.

Source: Hunskar GS, Rortveit G, Litleskare S, Eide GE, Hanevik K, Langeland N, Wensaas KA. Prevalence of fibromyalgia 10 years after infection with Giardia lamblia: a controlled prospective cohort study. Scand J Pain. 2021 Oct 21;22(2):348-355. doi: 10.1515/sjpain-2021-0122. PMID: 34679267. https://www.degruyter.com/document/doi/10.1515/sjpain-2021-0122/html (Full text)

Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation

Summary:

COVID survivors frequently experience lingering neurological symptoms that resemble cancer therapy-related cognitive impairment, a syndrome for which white-matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans.
Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared to SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis and elevated CCL11 at early timepoints, but after influenza only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.
Source: Anthony Fernández-Castañeda, Peiwen Lu, Anna C. Geraghty, Eric Song, MyoungHwa Lee, Jamie Wood, Michael R. O’Dea, Selena Dutton, Kiarash Shamardani, Kamsi Nwangwu, Rebecca Mancusi, Belgin Yalçın, Kathryn R. Taylor, Lehi AcostaAlvarez, Karen Malacon, Michael B. Keough, Lijun Ni, Pamelyn J. Woo, Daniel Contreras-Esquivel, Angus Martin Shaw Toland, Jeff R. Gehlhausen, Jon Klein, Takehiro Takahashi, Julio Silva, Benjamin Israelow, Carolina Lucas, Tianyang Mao, Mario A. Peña-Hernández, Alexandra Tabachnikova, Robert J. Homer, Laura Tabacof, Jenna Tosto-Mancuso, Erica Breyman, Amy Kontorovich, Dayna McCarthy, Martha Quezado, Hannes Vogel, Marco M. Hefti, Daniel P. Perl, Shane Liddelow, Rebecca Folkerth, David Putrino, Avindra Nath, Akiko Iwasaki, Michelle Monje. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation.  Cell (2022). Published: June 12, 2022 DOI:https://doi.org/10.1016/j.cell.2022.06.008 https://www.sciencedirect.com/science/article/pii/S0092867422007139 (Full text available as PDF file)

Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19

Abstract:

COVID-19 is primarily known as a respiratory disease caused by SARS-CoV-2. However, neurological symptoms such as memory loss, sensory confusion, severe headaches, and even stroke are reported in up to 30% of cases and can persist even after the infection is over (long COVID). These neurological symptoms are thought to be produced by the virus infecting the central nervous system, however we don’t understand the molecular mechanisms triggering them. The neurological effects of COVID-19 share similarities to neurodegenerative diseases in which the presence of cytotoxic aggregated amyloid protein or peptides is a common feature. Following the hypothesis that some neurological symptoms of COVID-19 may also follow an amyloid etiology we identified two peptides from the SARS-CoV-2 proteome that self-assemble into amyloid assemblies. Furthermore, these amyloids were shown to be highly toxic to neuronal cells. We suggest that cytotoxic aggregates of SARS-CoV-2 proteins may trigger neurological symptoms in COVID-19.

Source: Charnley, M., Islam, S., Bindra, G.K. et al. Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19. Nat Commun 13, 3387 (2022). https://doi.org/10.1038/s41467-022-30932-1 https://www.nature.com/articles/s41467-022-30932-1 (Full text)