Effects of Borrelia on host immune system: Possible consequences for diagnostics

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Abstract

Borreliosis, Lyme disease, is the fastest growing tick borne infection in the world. Annually 300,000 (0.094%) people are diagnosed in the USA.

Objective

To clarify and aid in the understanding of the indirect diagnostics of Borreliosis in the light of immune dysfunction.

Diagnosis is difficult not only due to multi-systemic and nonspecific nature of symptoms but also due to the indirect diagnostics assuming immuno-competence in all three stages of Borreliosis. Indirect diagnostics are the most common method of testing for Borreliosis as they are cheap and convenient. However due to wide variation in antigenicity of genospecies, the sensitivity and specificity of diagnostics can be questioned. Evidence is accumulating which suggests that immune dysregulation induced by Borrelia (and other tick borne infections) can impact the indirect diagnostics, especially in Stage 3. The direct detection of Borrelia using nucleotide amplification method is possible but wider usage of this method is difficult as it has high specificity and narrow sensitivity. In vitro culturing is ideal but difficult as Borrelia has fastidious growth requirements.

The immune status of the borreliosis patient needs to be considered, especially in Stage 3 in conjunction with clinical symptoms in the diagnosis. Borrelia has the ability to manipulate both the innate and active immunity and alter the cytokines secreted hence alter the path of the immune response. Immune parameters such as IFN-gamma/IL-10, lymphocyte markers, complement C3a, C4a, and total immunoglobulin levels may help to discriminate between stages and monitor treatment outcomes. The level of immune dysfunction in Stage 3 may depend on the number of co-infections delivered by a tick bite, such as Babesia, and Rickettsia, the genospecies of Borrelia, other pathogens, the patients’ biome and immunogenetics.

Section snippets

Symptoms

Borrelia infection can result in multi-organ disease and is non-pathognomonic except in subcutaneous presentation such as the erythema migrans (EM) rash. Symptoms range from asymptomatic to debilitating. They can imitate many chronic diseases including motor neurone disease [6], multiple sclerosis [7], Parkinson's disease [8], Alzheimer's [9] and fibromyalgia [10] and CFS [11].

Presentation depends on many factors including the stage of the disease [12] and genospecies (Table 2).

Stages of Borreliosis

Stage 1 (early localised) symptoms can begin within 3 days of the tick bite with flu-like symptoms, fever, headache, myalgia, joint pain, stiff neck, fatigue and EM rash, their occurrence dependent on the genospecies [13] (Table 2).

Stage 2 (early disseminated) occurs weeks to months after initial infection and can present with generalised lymphadenopathy and fatigue. Neurological manifestations may include encephalitis, cranial neuritis, radiculoneuritis, paresis, carditis and migratory

Immune evasion

Micro-organisms have developed sophisticated methods of facilitating survival in host. Borrelia, a spirochete bacterium, has evolved many strategies to ensure survival including utilising arthropod salivary proteins (sialostatin, Sal 15) to assist establishment of infection by inhibiting T and dendritic cells [16], [17]. Borrelia prefers micro-anaerobic environments where the immune surveillance is low such as the CNS, joints and skin. To survive in the host, Borrelia has adopted a

Immune dysregulation

There is a growing body of evidence in literature that indicate the presence of significant immune dysfunction in tick borne infections including Borreliosis. The level of immune dysfunction is determined by the host's immune system, number of tick bites, pathogen load, genospecies, strains and the number of co-infections delivered by the tick [24], [29], [30]. Alteration of Borrelia outer surface proteins (Osp), A–E expression inhibits complement activation which aids to establish infection

Diagnostics

Interpretation of diagnostic results needs be in the context of symptomology, risk of tick exposure and/or travel history. Immune status needs to be considered in diagnosis, particularly in suspected Stage 3 Borreliosis. This may impact on the sensitivity of diagnostic tests that are based upon lymphocyte (B or T cell) mediated immune response to Borrelia.

C6 antigen assay – VlsE C6 peptide assay

The C6 antigen assay (26 mer peptide from the sixth invariable region of VlsE) of B. burgdorferi [61] should be sensitive and specific as this region is conserved across the genus. In USA C6 assay failed to detect 1 out 3 ribosomal spacer defined genotypes of Borrelia [74]. This would translate to 33% failure of the C6 antigen assay in the USA East Coast the centre of B. burgdorferi sensu stricto infection. As a result a single C6 test approach recombinant VslE immunoassay [75], or immunoblot

Direct Diagnostic Techniques

Commonly employed Direct Diagnostic Techniques include culture from tissue specimens, microscopy techniques and Nucleic Acid Amplification Techniques (NAAT).

Summary

Understanding the immune dysregulation induced by Borrelia and co-infections can aid the interpretation of diagnostics and improve diagnosis of Borreliosis. Present diagnostics do not discriminate between different stages of Borreliosis. In addition indirect diagnostics reliant on the immune response assume immuno-competence of the host in all stages of Borreliosis. This document has tried to highlight that apart from immune evasion aided by tick saliva in Stages 1 and 2, there is ongoing

Acknowledgment

Extremely grateful for the contributions of Ann Mitrovic to the compilation and editing of this manuscript.

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