Erol Fikrig’s research while affiliated with Yale University and other places

Lyme disease, caused by Borrelia burgdorferi , is the most common tick-borne infection in the United States. Arthritis is a major clinical manifestation of infection, and synovial tissue damage has been attributed to the excessive pro-inflammatory responses. The secretory leukocyte protease inhibitor (SLPI) promotes tissue repair and exerts anti-inflammatory effects. The role of SLPI in the development of Lyme arthritis in C57BL/6 mice, which can be infected with B. burgdorferi , but only develop mild joint inflammation, was therefore examined. SLPI -deficient C57BL/6 mice challenged with B. burgdorferi had a higher infection load in the tibiotarsal joints and marked periarticular swelling, compared to infected wild type control mice. The ankle joint tissues of B. burgdorferi- infected SLPI -deficient mice contained significantly higher percentages of infiltrating neutrophils and macrophages. B. burgdorferi -infected SLPI -deficient mice also exhibited elevated serum levels of IL-6, neutrophil elastase, and MMP-8. Moreover, using a recently developed BASEHIT ( BA cterial S election to E lucidate H ost-microbe I nteractions in high T hroughput) library, we found that SLPI directly interacts with B. burgdorferi . These data demonstrate the importance of SLPI in suppressing periarticular joint inflammation in Lyme disease.

Lyme disease, caused by Borrelia burgdorferi , is the most common tick-borne infection in the United States. Arthritis is a major clinical manifestation of infection, and synovial tissue damage has been attributed to the excessive pro-inflammatory responses. The secretory leukocyte protease inhibitor (SLPI) promotes tissue repair and exerts anti-inflammatory effects. The role of SLPI in the development of Lyme arthritis in C57BL/6 mice, which can be infected with B. burgdorferi , but only develop mild joint inflammation, was therefore examined. SLPI -deficient C57BL/6 mice challenged with B. burgdorferi had a higher infection load in the tibiotarsal joints and marked periarticular swelling, compared to infected wild type control mice. The ankle joint tissues of B. burgdorferi- infected SLPI -deficient mice contained significantly higher percentages of infiltrating neutrophils and macrophages. B. burgdorferi -infected SLPI -deficient mice also exhibited elevated serum levels of IL-6, neutrophil elastase, and MMP-8. Moreover, using a recently developed BASEHIT ( BA cterial S election to E lucidate H ost-microbe I nteractions in high T hroughput) library, we found that SLPI directly interacts with B. burgdorferi . These data demonstrate the importance of SLPI in suppressing periarticular joint inflammation in Lyme disease.

Plasmodium, the causative agents of malaria, are obtained by mosquitoes from an infected human. Following Plasmodium acquisition by Anopheles gambiae, mosquito gamma-interferon-inducible lysosomal thiol reductase (mosGILT) plays a critical role in its subsequent sporogony in the mosquito. A critical location for this development is the midgut, a tissue we show expresses mosGILT. Using membrane-feeding and murine infection models, we demonstrate that antibodies against mosGILT reduce the number of P. falciparum and P. berghei oocysts in the midgut and the infection prevalence of both species in the mosquito. mosGILT antibodies act in the mosquito midgut, specifically impacting the Plasmodium oocyst stage. Targeting mosGILT can therefore interfere with the Plasmodium life cycle in the mosquito and potentially serve as a transmission-blocking vaccine.

Lyme disease, caused by Borrelia burgdorferi, is transmitted to humans by Ixodes ticks. CCL17 is a potent chemokine that plays important roles in diverse illnesses, including autoimmune and infectious diseases. CCL17 knockout (KO) mice, infected with B. burgdorferi, had a reduced pathogen load in the heart, compared to control animals. Mice lacking CCL17 also showed signs of immune alteration upon B. burgdorferi infection, including diverse serum levels of proinflammatory cytokines and fewer monocytes and macrophages infiltration. CCL17 also interacts directly with B. burgdorferi, the first demonstration that this chemokine has an affinity for a vector-borne pathogen.

Lyme disease, caused by Borrelia burgdorferi , is the most common tick-borne infection in the United States. Arthritis is a major clinical manifestation of infection, and synovial tissue damage has been attributed to the excessive pro-inflammatory responses. The secretory leukocyte protease inhibitor (SLPI) promotes tissue repair and exerts anti-inflammatory effects. The role of SLPI in the development of Lyme arthritis in C57BL/6 mice, which can be infected with B. burgdorferi , but only develop mild joint inflammation, was therefore examined. SLPI -deficient C57BL/6 mice challenged with B. burgdorferi had a higher infection load in the tibiotarsal joints and marked periarticular swelling, compared to infected wild type control mice. The ankle joint tissues of B. burgdorferi- infected SLPI -deficient mice contained significantly higher percentages of infiltrating neutrophils and macrophages. B. burgdorferi -infected SLPI -deficient mice also exhibited elevated serum levels of IL-6, neutrophil elastase, and MMP-8. Moreover, using a recently developed BASEHIT ( BA cterial S election to E lucidate H ost-microbe I nteractions in high T hroughput) library, we found that SLPI directly interacts with B. burgdorferi . These data demonstrate the importance of SLPI in suppressing periarticular joint inflammation in Lyme disease.

Background Measuring malaria transmission intensity using the traditional entomological inoculation rate is difficult. Antibody responses to mosquito salivary proteins like SG6 have been used as biomarkers of exposure to Anopheles mosquito bites. Here, we investigate 4 mosquito salivary proteins as potential biomarkers of human exposure to mosquitoes infected with Plasmodium falciparum: mosGILT, SAMSP1, AgSAP, and AgTRIO. Methods We tested population-level human immune responses in longitudinal and cross-sectional plasma from individuals with known P falciparum infection from low- and moderate-transmission areas in Senegal using a multiplexed magnetic bead–based assay. Results AgSAP and AgTRIO were the best indicators of recent exposure to infected mosquitoes. Antibody responses to AgSAP, in a moderate-endemicity area, and to AgTRIO in both low- and moderate-endemicity areas, were significantly higher than nonendemic controls. No antibody responses significantly differed between low- and moderate-transmission areas, or between equivalent groups during and outside the malaria transmission seasons. AgSAP and AgTRIO reactivity peaked 2–4 weeks after clinical P falciparum infection and declined 3 months after infection. Conclusions Reactivity to AgSAP and AgTRIO reflects exposure to infectious mosquitoes or recent bites rather than general mosquito exposure, highlighting their promise for incorporation into multiplexed assays for serosurveillance of population-level changes in P falciparum–infected mosquito exposure.

The protein disulfide isomerase (PDI) family is a group of enzymes that have thiol-disulfide oxidoreductase, disulfide isomerase, and redox-dependent chaperone activities. PDIs facilitate diverse infections in mammalian hosts by directly binding to pathogens, immunomodulation, or enabling microbial invasion of host cells. PDI homologs within pathogens are also potential virulence factors. However, whether PDIs within blood-feeding ticks influence microbial infection remains unknown. In this study, we investigated the role of Ixodes scapularis PDIs, on the Lyme disease agent, Borrelia burgdorferi. I. scapularis has five PDIs (IsPDIs), and IsPDIA6 gene expression is reduced upon B. burgdorferi infection in the tick. IsPDIA6-mediated trypsin inhibitor gene expression contributes to B. burgdorferi colonization within the tick midgut. IsPDIA6 is also secreted into the host during tick feeding, alters cytokine/chemokine expression at the tick bite site, and influences the initial stage of bacterial infection in mice. These data demonstrate that a PDI from a blood-feeding vector plays a role in the life cycle of an extracellular pathogen. IMPORTANCE Vector-borne diseases are a leading cause of death and illness worldwide, and more than 80% of the global population live in areas at risk from at least one major vector-borne disease. In this study, we demonstrate a dual role of a specific Ixodes tick protein disulfide isomerase (PDI) in inhibiting the ability of the Lyme disease agent to colonize ticks and also in enhancing the initial stage of spirochete infection of mice. This study represents a novel conceptual advancement that a PDI from a blood-feeding vector plays important roles in the life cycle of an extracellular pathogen.

The Aedes aegypti mosquito plays a critical role in the transmission of viral diseases, including Zika virus, which poses significant public health challenges. Understanding the complex interactions between mosquitoes and viruses is paramount for the development of effective control strategies. In this study, we demonstrate that silencing the A. aegypti adiponectin receptor-like protein (AaARLP) results in a reduction of Zika virus infection. Transcriptomic analysis identified alterations in several trypsin genes and further revealed that AaARLP-knockdown mosquitoes had diminished trypsin activity. Moreover, silencing of selected trypsins resulted in a similar delay in Zika virus infection in mosquitoes, further highlighting the connection between the AaARLP and trypsin. Overall, our findings demonstrate that AaARLP signaling is important for Zika virus infection of A. aegypti. IMPORTANCE Arboviruses pose a significant threat to public health, with mosquitoes, especially Aedes aegypti, being a major vector for their transmission. Gaining insight into the complex interaction between mosquitoes and viruses is essential to build successful control strategies. In this study, we identified a novel pathway connecting the A. aegypti adiponectin receptor-like protein and its association with trypsin, key enzymes involved in blood digestion. Furthermore, we demonstrated the significance of signaling via the adiponectin receptor-like protein in virus infection within the mosquito. Together, our discoveries illuminate mosquito metabolic pathways essential in viral infection.