Correlation between COVID-19 severity and previous exposure of patients to Borrelia spp. | Scientific Reports – Nature.com

In this study we investigated potential correlations between detected antibody levels indicating exposure to Borrelia and the risk of increased severity of COVID-19. Previous exposure to Borrelia was identified by multi-antigenic serological testing, and it revealed that increased levels of Borrelia-specific IgGs strongly correlated with COVID-19 severity and with the risk of hospitalization (Fig.1 and 3, Supplementary Tables S1 and S2). For Borrelia-specific IgMs, correlations were weaker and mostly insignificant (Fig.2 and Supplementary Fig. S3, Supplementary Tables S3 and S4).

Typically, pathogen-specific IgM increases at the early stage of infection, while IgG development takes more time. In borreliosis, at the early stage of infection (24weeks) the immunological system detects only a few antigens of Borrelia, e.g. p41 (flagellin) and Osp proteins (outer surface proteins), targeted by IgM antibodies. Borrelia-specific IgGs, in turn, can be observed several weeks after the tick bite, and their increased serum concentration can remain for a long time, even after the resolution of clinical symptoms. OspC, OspA, and p41 are considered the most immunogenic proteins of B. burgdorferi19,20,21; consistently, in this study IgGs targeting these antigens were also the most frequent and they reached the highest levels (Fig.1). Other important targets for IgG diagnostics include VisE, p83, p58, and p17 19,20,21, also detected in this study. Interestingly, in many patients we observed antibodies targeting different species (e.g. B. burgdorferi sensu stricto, and at the same time B. afzelii, and/or B. garinii). This may reflect some cross-reactivity of antibodies, but likely it may result from co-infections with more than one species, which according to the literature may also occur 22. Also, severe COVID-19 patients demonstrated significantly higher levels of IgG specific to Anaplasma (Fig.1), which is often co-transmitted with Borrelia by ticks. This further supports the suggestion that increased risks in COVID-19 are linked to a history of tick bites and related infections (Fig.4).

Risks in COVID-19 are linked to a history of tick bites and related infections.

Important limitations should be considered for a full understanding of this studys results. First, diagnostics of Lyme disease (active borreliosis) is still difficult and often unclear. Laboratory testing should be considered in conjunction with potential exposure and compatible clinical symptoms10; data on patients history of tick bites and on potential borreliosis-related symptoms were not available here. Particularly severe COVID-19 patients under intensive care were not able to give them. Thus, in the investigated group at least some individuals may demonstrate immunological memory of previous Borrelia infection/s but not an active disease. On the other hand, difficulties with rapid and unambiguous diagnosis may lead to some Borrelia-infected patients going untreated, with the pathogen affecting their health condition even for a long time.

Second, although this study demonstrated a significant correlation between serum levels of anti-Borrelia antibodies and COVID-19 severity observed in the same individuals, a correlation cannot be assumed to indicate causation. One cannot exclude that there was an unidentified primary factor that in these patients caused both higher vulnerability to Borrelia infection and to severe COVID-19. This could possibly be immunodeficiency, other physiological disorders or comorbidities. Of note, patients in the severe COVID cohort were likely to have more comorbidities than those in the other two groups. For instance, obesity has been indicated as associated with the risk of COVID-19-related hospitalizations and death23. In Lyme disease, obesity was associated with attenuated and delayed IgG responses to B. burgdorferi, thus suggesting less efficient protection from adaptive immunity in obese individuals24. Since these patients demonstrated an efficient antibody response to SARS-CoV-2 (Fig.1), this issue calls for further research. Demographic parameters, in turn, have been agreed between groups (Supplementary Fig. S2), so for instance elderly age was not a contributing factor here.

Alternatively, prolonged Lyme disease might affect the immune system, decreasing its efficacy in antiviral responses in the viral infection. This has never been demonstrated yet, though important effects that Borrelia may have on the immune system have been described25,26. Furthermore, one of the possible explanations for studied relationship may be a more detailed insight into the mechanisms of the immune system, more specifically the Toll-like receptor pathway (TLR), whose innate immunity receptors recognize ligands derived from bacteria, fungi, and viruses27. Studies indicate that the TLR pathway mediates, at least in part, the release of inflammatory mediators in human monocytes stimulated with live B. burgdorferi spirochetes28. Similarly, the role of TLR receptors has been described in SARS-CoV-2 infection, which contributes to the elimination of viruses, but it can also harm the host due to persistent inflammation and tissue destruction29. Particularly, B. burgdorferi has been demonstrated to interact with TLR1/TLR2 heterodimers with resulting stimulation of inflammatory response, including increased inflammatory cytokine markers, like IL-6 and TNF-28. The same molecular pathway is targeted by SARS-CoV-2, where stimulation via TLR1 and TLR2 has been indicated as the key factor of excessively upregulated cytokine response and its harmful effects within severe COVID-1930,31. This suggests that co-stimulation from both B. burgdorferi and SARS-CoV-2 may result in even more pronounced excessive inflammatory response and a higher risk of severe COVID-19. This hypothesis needs to be further verified in future studies.

In spite of above mentioned important reservations and considerations, a strong link between detected anti-Borrelia antibodies and COVID-19 severity was observed in this study (Fig.1, 2, and 3). This was further supported by post-hoc analysis of IgG targeting selected antigens of Borrelia. These antigens included Osp proteins, p41, and VlsE, being highly immunogenic19,20,21 and important in the life cycle of spirochetes; they are engaged in bacterial colonization of ticks and mammals, virulence, and immune evasion by Borrelia32,33,34. The analysis with multivariant logistic regression revealed that increased levels of IgG targeting Osp proteins (only) can be significant predictors of hospitalization due to COVID-19; in this study OspB, OspC B. burgdorferi sensu stricto, and OspC B. spielmanii demonstrated significance in this model (Supplementary Fig. S4, Supplementary Table S5).

To the best of our knowledge, this is the first observation that suggests links between Lyme disease and COVID-19 prognostics. Screening for antibodies targeting Borrelia may contribute to accurately assessing the odds of hospitalization for SARS-CoV-2 infected patients. Though mechanisms of this association are not clear yet, it may help in establishing optimal treatment schedules and in efficient predictions of individual patients prognostics, supporting efforts for efficient control of COVID-19.

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Correlation between COVID-19 severity and previous exposure of patients to Borrelia spp. | Scientific Reports - Nature.com