Correlation between the severity of COVID-19 and previous exposure of patients to Borrelia spp.

In this study, we explored possible correlations between detected antibody levels indicative of 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 elevated levels of Borrelia-specific IgGs strongly correlated with the severity of COVID-19 and with the risk of hospitalization (Fig. 1 and 3, Supplementary Tables S1 and S2). In front of Borrelia-specific IgMs, correlations were weaker and mostly insignificant (Figure 2 and Supplementary Figure S3, Supplementary Tables S3 and S4).

Typically, pathogen-specific IgM increases in the early stage of infection, while IgG development takes more time. In borreliosis, the immune system detects only a few antigens of . in the early stage of infection (2-4 weeks). Borreliae.g. p41 (flagellin) and Osp proteins (outer surface proteins), the target of IgM antibodies. Borrelia-specific IgGs, in turn, can be observed several weeks after the tick bite and their elevated serum concentration can persist for a long time even after the clinical signs have disappeared. OspC, OspA and p41 are considered to be the most immunogenic proteins of B. burgdorferi19,20,21; consistently in this study, IgGs targeting these antigens were also the most abundant and reached the highest levels (Fig. 1). Other important targets for IgG diagnostics are VisE, p83, p58 and p17 19,20,21, also detected in this study. Interestingly, we saw antibodies targeting different species (e.g., B. burgdorferi sensu stricto, and at the same time B. afzeliiand/or B. garini). This may reflect some antibody cross-reactivity, but it likely could be due to co-infections with more than one species, which can also occur according to the literature 22. Also, severe COVID-19 patients showed significantly higher levels of IgG specific for Anaplasm (Fig. 1), which is often shipped together with Borrelia by sign. This further supports the suggestion that increased risks in COVID-19 are related to a history of tick bites and related infections (Fig. 4).

Figure 4
figure 4

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

Important limitations must be considered for a full understanding of the results of this study. Firstly, the diagnosis of Lyme disease (active borreliosis) is still difficult and often unclear. Laboratory testing should be considered in conjunction with potential exposure and compatible clinical signs10; data on the history of tick bites in patients and on possible symptoms related to borreliosis were not available here. Especially severe COVID-19 patients in intensive care could not give them. Thus, in the study group, at least some individuals may have immunological memory of previous Borrelia infection(s), but no active disease. On the other hand, problems with a quick and unambiguous diagnosis can lead to a Borrelia-infected patients who remain untreated, where the pathogen even affects their health status for a long time.

Second, although this study showed a significant correlation between serum levels of anti-Borrelia antibodies and severity of COVID-19 observed in the same individuals, a correlation cannot be assumed to indicate causation. It cannot be excluded that there was an unidentified primary factor that contributed to both a higher vulnerability to Borrelia infection and to severe COVID-19. This could possibly be an immune deficiency, other physiological conditions or comorbidities. Note that patients in the severe COVID cohort likely had more comorbidities than those in the other two groups. For example, it has been indicated that obesity is 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. burgdorferisuggesting that there is less efficient protection against adaptive immunity in obese individuals24. Since these patients showed an efficient antibody response to SARS-CoV-2 (Fig. 1), this issue calls for further investigation. Demographic parameters, in turn, were agreed between groups (Supplementary Figure S2), so, for example, older age was not a contributing factor here.

Alternatively, prolonged Lyme disease can compromise the immune system, decreasing its effectiveness in antiviral responses to the viral infection. This has never been demonstrated, although important effects that Borrelia may have on the immune system have been described25.26. In addition, one of the possible explanations for the studied relationship may be a more detailed understanding of the mechanisms of the immune system, more specifically the Toll-like receptor pathway (TLR), whose innate immune receptors recognize ligands derived from bacteria, fungi and viruses.27. Studies show that the TLR pathway, at least in part, inhibits the release of inflammatory mediators in human monocytes treated with live B. burgdorferi spirochetes28. Likewise, 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 ongoing inflammation and tissue destruction.29. special, B. burgdorferi has been shown to interact with TLR1/TLR2 heterodimers with resulting stimulation of the inflammatory response, including increased inflammatory cytokine markers, such as IL-6 and TNF-α28. The same molecular pathway is targeted by SARS-CoV-2, with stimulation via TLR1 and TLR2 indicated as the key factor of an over-regulated cytokine response and its deleterious effects in severe COVID-1930.31. This suggests that costimulation of both B. burgdorferi and SARS-CoV-2 may result in an even more pronounced over-inflammatory response and a higher risk of severe COVID-19. This hypothesis should be further verified in future studies.

Despite the important caveats and considerations mentioned above, there is a strong association between detected anti-Borrelia antibodies and severity of COVID-19 were observed in this study (Fig. 1, 2 and 3). This was further supported by post-hoc analysis of IgG targeting selected antigens from Borrelia. These antigens include Osp proteins, p41 and VlsE, which are highly immunogenic19,20,21 and important in the life cycle of spirochetes; they are involved in bacterial colonization of ticks and mammals, virulence and immune evasion by Borrelia32,33,34. The multivariate logistic regression analysis revealed that elevated levels of IgG targeting Osp proteins (alone) may be significant predictors of hospitalization due to COVID-19; in this study OspB, OspC B. burgdorferi sensu stricto and OspC B. spielmanii showed significance in this model (Supplementary Figure S4, Supplementary Table S5).

To our knowledge, this is the first observation to suggest links between Lyme disease and the prognosis of COVID-19. Antibody Targeting Screening Borrelia may help to accurately estimate the risk of hospitalization for SARS-CoV-2 infected patients. While the mechanisms of this association are not yet clear, it may help establish optimal treatment regimens and make efficient predictions of individual patients’ prognosis, supporting efforts to efficiently control COVID-19.

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