A<i>Borrelia burgdorferi</i>Surface-Exposed Transmembrane Protein Lacking Detectable Immune Responses Supports Pathogen Persistence and Constitutes a Vaccine Target

Kung, Faith; Kaur, Savneet; Smith, Alexis A.; Yang, Xiuli; Wilder, Cara N.; Sharma, Kavita; Büyüktanir, Özlem; Pal, Utpal

doi:10.1093/infdis/jiw013

Cited by 37 publications

(54 citation statements)

References 40 publications

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“…Additionally, using a mutant and complemented strains, we determined that BB0406 is not sufficient to restore mouse infectivity in a strain lacking the expression of both BB0405 and BB0406. In contrast, BB0405 could restore infectivity to the mutant, which was consistent with recently reported findings by Kung and coworkers (35). Finally, when we assessed the role of BB0405 or BB0406 in factor H binding and serum resistance, we found no evidence that either OMP could bind factor H, consistent with our observation that a mutant lacking the expression of BB0405 and BB0406 was not serum sensitive.…”

supporting

confidence: 92%

“…It may be that BB0406 is poorly immunogenic, which resulted in the delayed humoral immune response observed. In fact, it has been reported that antibodies against BB0405 do not develop for at least 1 month after mice are infected with B. burgdorferi (35). While we did not examine sera from a time point before 6 weeks postinfection, it seems possible that both BB0405 and BB0406 are poorly immunogenic in the mammalian host, and the delayed antibody response allows these specific OMPs to remain hidden from the immune system during the acute phase of infection.…”

Section: Discussionmentioning

confidence: 93%

“…The genes encoding these OMPs were recently shown to be cotranscribed (32,35), suggesting that these OMPs would be coexpressed. However, in this study, we observed a difference in the temporal antibody response to the individual BB0405 and BB0406 OMPs, suggesting that they may not be coordinately expressed during infection.…”

Section: Discussionmentioning

confidence: 99%

“…Outer membrane protein BB0405 was initially identified in a screen for outer surface proteins (34) and was more recently characterized for its physicochemical properties (32) and role in B. burgdorferi virulence (35). Additional studies on BB0405 orthologs of other borrelial genospecies have indicated that this OMP binds human factor H (36,37), suggesting that BB0405 and its orthologs play a role in serum resistance.…”

mentioning

confidence: 99%

“…While a recent study indicated that BB0405 is required for mammalian infectivity (35), the role that BB0406 may play in B. burgdorferi virulence and infection has not been studied. Therefore, we next sought to examine the role of BB0406 in infectivity.…”

mentioning

confidence: 99%

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Outer Membrane Proteins BB0405 and BB0406 Are Immunogenic, but Only BB0405 Is Required for Borrelia burgdorferi Infection

2017

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We recently identified the Borrelia burgdorferi outer membrane protein (OMP) BB0406 and found that the gene encoding this OMP was cotranscribed with the gene encoding the OMP BB0405. Interestingly, BB0405 and BB0406 share 59% similarity and are grouped into the same B. burgdorferi paralogous gene family. Given their overall similarity, it is plausible that both OMPs have similar or overlapping functions in this pathogenic spirochete. BB0405 was recently shown to be required for mammalian infection despite the observations that BB0405 is poorly immunogenic and not recognized during mouse or human infection. BB0405 orthologs have also been shown to bind the complement regulator protein factor H. Therefore, to better elucidate the role of BB0405 and its paralog BB0406 during infection and in serum resistance, we examined both proteins in animal infection, factor H binding, and serum sensitivity assays. Our combined results suggest that BB0405-and BB0406-specific antibodies are borreliacidal and that both OMPs are immunogenic during nonhuman primate infection. Additionally, while BB0405 was found to be required for establishing mouse infection, BB0406 was not found to be essential for infectivity. In contrast to data from previous reports, however, neither OMP was found to bind human factor H or to be required for enhancing serum resistance of B. burgdorferi in vitro.KEYWORDS Borrelia burgdorferi, Lyme disease, outer membrane proteins, spirochete L yme disease is a multisystem infection caused by pathogenic spirochetes belonging to the Borrelia burgdorferi sensu lato complex (1, 2). It is the most prevalent arthropod-borne disease in the United States and has become a major public health concern (3, 4). The enzootic life cycle of the spirochete is complex and involves tick vectors of the Ixodes genus that transmit the spirochete to a wide range of mammalian host reservoirs in nature. Humans are accidental hosts and play no significant role in the spirochete life cycle (5). The primary manifestations of Lyme disease are a localized rash, termed erythema migrans, and flu-like symptoms (6). In the absence of antibiotic treatment, spirochetes can disseminate to multiple organs, including the heart, joints, skin, and nervous system (7). To disseminate to these distant sites, the spirochete must evade serum-mediated killing and the subsequent adaptive immune response that ensues in the mammalian host (5,6,8).Given that B. burgdorferi is an extracellular pathogen, the outer membrane (OM) of this organism is the interface between the spirochete and the host during infection. The two major classes of proteins present in the borrelial OM are (i) outer surface lipoproteins (Osps) that are anchored to the outer leaflet of the OM bilayer by their N-terminal lipid moieties and (ii) integral outer membrane proteins (OMPs) that contain membrane-spanning domains. Membrane-anchored Osps have been well studied be-

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supporting

confidence: 92%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Outer Membrane Proteins BB0405 and BB0406 Are Immunogenic, but Only BB0405 Is Required for Borrelia burgdorferi Infection

2017

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Visualization of the Dynamics of Invasion and Intravasation of the Bacterium That Causes Lyme Disease in a Tissue Engineered Dermal Microvessel Model

et al. 2022

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Lyme disease is a tick‐borne disease prevalent in North America, Europe, and Asia. Despite the accumulated knowledge from epidemiological, in vitro, and in animal studies, the understanding of dissemination of vector‐borne pathogens, such as Borrelia burgdorferi (Bb), remains incomplete with several important knowledge gaps, especially related to invasion and intravasation into circulation. To elucidate the mechanistic details of these processes a tissue‐engineered human dermal microvessel model is developed. Fluorescently labeled Bb are injected into the extracellular matrix (ECM) to mimic tick inoculation. High resolution, confocal imaging is performed to visualize the sub‐acute phase of infection. From analysis of migration paths no evidence to support adhesin‐mediated interactions between Bb and ECM components is found, suggesting that collagen fibers serve as inert obstacles to migration. Intravasation occurs at cell–cell junctions and is relatively fast, consistent with Bb swimming in ECM. In addition, it is found that Bb alone can induce endothelium activation, resulting in increased immune cell adhesion but no changes in global or local permeability. Together these results provide new insight into the minimum requirements for Bb dissemination and highlight how tissue‐engineered models are complementary to animal models in visualizing dynamic processes associated with vector‐borne pathogens.

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Vaccines Against Vector-Borne Diseases

Kitsou

Pal

2021

Vaccine Design

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ABorrelia burgdorferiSurface-Exposed Transmembrane Protein Lacking Detectable Immune Responses Supports Pathogen Persistence and Constitutes a Vaccine Target

Cited by 37 publications

References 40 publications

Outer Membrane Proteins BB0405 and BB0406 Are Immunogenic, but Only BB0405 Is Required for Borrelia burgdorferi Infection

Outer Membrane Proteins BB0405 and BB0406 Are Immunogenic, but Only BB0405 Is Required for Borrelia burgdorferi Infection

Visualization of the Dynamics of Invasion and Intravasation of the Bacterium That Causes Lyme Disease in a Tissue Engineered Dermal Microvessel Model

Vaccines Against Vector-Borne Diseases

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