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

In this study, we investigated potential correlations between detected antibody levels indicating exposure to Borrelia and the risk of increased severity of COVID-19. Exposure prior to Borrelia was identified by multi-antigen serological tests, and it revealed that increased levels of Borrelia– Specific IgG strongly correlated with the severity of COVID-19 and the risk of hospitalization (Fig. 1 and 3, Supplementary Tables S1 and S2). For Borrelia-specific IgM, the correlations were weaker and generally insignificant (Fig. 2 and Supplementary Fig. S3, Supplementary Tables S3 and S4).

Typically, pathogen-specific IgM increases in the early stage of infection, while IgG development takes longer. In borreliosis, at the early stage of the infection (2 to 4 weeks), the immunological system detects only a few antigens of Borreliafor example the proteins p41 (flagellin) and Osp (outer surface proteins), targeted by IgM antibodies. Borrelia-specific IgG, in turn, can be observed several weeks after the tick bite, and their increased serum concentration can persist for a long time, even after the resolution of clinical symptoms. OspC, OspA and p41 are considered to be the most immunogenic proteins in 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 diagnosis 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. afzeliand or B. garini). This may reflect some antibody cross-reactivity, but this may likely result from co-infections with more than one species, which the literature suggests may also occur. 22. Additionally, patients with severe COVID-19 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 of COVID-19 are related to a history of tick bites and associated infections (Fig. 4).

Figure 4

Risks from COVID-19 are related to a history of tick bites and associated infections.

Important limitations should be considered for a full understanding of the results of this study. First, the diagnosis of Lyme disease (active borreliosis) is still difficult and often unclear. Laboratory tests should be considered in conjunction with potential exposure and compatible clinical symptomsten; data on patients’ tick-bite histories and potential borreliosis-related symptoms were not available here. Particularly severe COVID-19 patients in intensive care could not give them. Thus, in the group studied, at least some individuals may demonstrate an immunological memory of Borrelia infection(s) but not active disease. On the other hand, the difficulties of rapid and unambiguous diagnosis can lead to certain Borrelia-infected patients are not treated, the pathogen affecting their state of health even for a long time.

Second, although this study demonstrated 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 is an unidentified primary factor which, in these patients, caused both a greater vulnerability to Borrelia infection and severe COVID-19. It can be an 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 example, obesity has been shown to be associated with the risk of COVID-19-related hospitalizations and deaths.23. In Lyme disease, obesity was associated with attenuated and delayed IgG responses B. burgdorferithus suggesting less effective protection against adaptive immunity in obese individuals24. Since these patients demonstrated an effective antibody response to SARS-CoV-2 (Fig. 1), this question calls for further investigation. Demographic parameters, in turn, were agreed between the groups (Supplementary Fig. S2), so, for example, the age of the elderly was not a contributing factor here.

Alternatively, prolonged Lyme disease could affect the immune system, decreasing its effectiveness in antiviral responses in viral infection. This has never yet been demonstrated, even if significant effects which Borrelia may have on the immune system have been described25.26. Moreover, one of the possible explanations for the studied relationship could be a more detailed insight into the mechanisms of the immune system, more specifically the Toll-like receptor (TLR) pathway, whose innate immunity receptors recognize derived ligands of bacteria, fungi and viruses.27. Studies indicate that the TLR pathway mediates, at least in part, the release of inflammatory mediators in human monocytes stimulated with 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 destruction.29. Notably, B. burgdorferi has been shown to interact with TLR1/TLR2 heterodimers with resultant stimulation of the inflammatory response, including an increase in inflammatory cytokine markers, such as IL-6 and TNF-α28. The same molecular pathway is targeted by SARS-CoV-2, where stimulation via TLR1 and TLR2 has been indicated as the key driver for an overregulated cytokine response and its harmful effects in severe cases of COVID. -1930.31. This suggests that co-stimulation of both B. burgdorferi and SARS-CoV-2 may lead to an even more pronounced excessive inflammatory response and higher risk of severe COVID-19. This hypothesis still needs to be verified in future studies.

Despite the important reservations and considerations mentioned above, a strong link between anti-Borrelia antibodies and severity of COVID-19 were observed in this study (Fig. 1, 2 and 3). This was confirmed by post-hoc analysis of IgGs targeting selected antigens from Borrelia. These antigens included Osp, p41 and VlsE proteins, 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. Multivariate logistic regression analysis 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 significance demonstrated in this model (Supplementary Fig. S4, Supplementary Table S5).

To our knowledge, this is the first observation that suggests links between Lyme disease and COVID-19 prognoses. Screening for antibodies targeting Borrelia can help to accurately assess the chances of hospitalization of patients infected with SARS-CoV-2. Although the mechanisms of this association are not yet clear, it may help establish optimal treatment schedules and effective predictions of individual patient prognoses, supporting efforts for effective control of COVID-19.