Biology subjects

Fikrig, E.

Publications and source records attributed to Fikrig, E..

10 recordsLinked to original sources

bioRxiv2026

Engineering Upd-like to broadly restrict arbovirus infection and vector competence in mosquitoes

The global expansion of mosquito-borne viruses poses a growing threat to public health, yet the endogenous signals that activate antiviral immunity in mosquito vectors remain incompletely understood. Here, we identify Aedes aegypti Upd as an activator of JAK/STAT signaling that restricts arbovirus infection. Loss of Upd increased infection and dissemination of the flaviviruses ZIKV and DENV, as well as the alphavirus SINV, whereas blood meal inducible midgut overexpression reduced ZIKV and SINV infection. Mechanistically, Upd associated with the extracellular region of the Domeless (Dome) receptor, and Upd deficiency markedly reduced STAT phosphorylation and nuclear accumulation in the midgut. Upd expression was transiently induced in the midgut by an uninfected blood meal but remained elevated following ZIKV challenge, linking physiological responses to blood feeding with antiviral defense. In mammal mosquito transmission models, Upd overexpression reduced viral acquisition from infected hosts, whereas Upd deficiency enhanced viral dissemination and increased transmission following systemic infection. Together, these findings identify Upd as an endogenous regulator of mosquito JAK/STAT signaling and provide proof of principle that temporally targeted Upd expression can reduce arbovirus susceptibility and vector competence.

microbiology↗

bioRxiv2026

Borrelia Burgdorferi binds Serum Amyloid A and Modulates Subcutaneous Adipose Tissue Immune Signaling

Borrelia burgdorferi causes over 470,000 infections annually [1]. Following a tick bite, Borrelia spirochetes replicate in human skin and disseminate through tissues, including subcutaneous adipose tissue. Adipose tissue is a complex organ containing non-immune and immune cells that play a significant role in the immune response [2], yet little is known about adipose tissue signaling after Borrelia infection. We investigated the landscape of immune signaling within adipose tissue-resident cells during Borrelia infection in human tissue (skin and adipose tissue) ex vivo. Immune pathways overall were downregulated in adipose tissue during Borrelia infection. Despite this, adipose stem/progenitor cells exhibited increased pro-inflammatory and extracellular matrix (ECM)-related signaling (IL-6, MIF, collagen, laminin, fibronectin), positioning them as key hubs of intercellular communication during infection. Myeloid lineage cells showed cluster-specific upregulation of immune genes such as IL1B and TNF. Network analyses highlighted laminin, and strong outgoing MIF signals in all adipose-resident cell clusters. Among the identified genes modulated after Borrelia infection, we observed reduced expression levels of serum amyloid A in adipose tissue-resident cells, a marker typically elevated in Lyme disease patient serum during acute infection. Here, we show that human serum amyloid A1 and serum amyloid A2 directly bind B. burgdorferi spirochetes, using flow cytometry. Functionally, serum amyloid A2 reduces spirochete viability in vitro in a dose-dependent manner and enhances opsonization and phagocytosis by macrophages. Together, these findings show that adipose tissue is a site of active immune signaling in the setting of Borrelia infection and identifies SAA as a host defense factor against Borrelia.

immunology↗

bioRxiv2024

Secretory leukocyte protease inhibitor influences periarticular joint inflammation in B. burgdorferi-infected mice

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 (BActerial Selection to Elucidate Host-microbe Interactions in high Throughput) 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.

microbiology↗

bioRxiv2023

Anopheles gambiae mosGILT regulates innate immune genes and zpg expression

Gene-edited mosquitoes lacking a gamma-interferon-inducible lysosomal thiol reductase-like protein, namely (mosGILTnull) have lower Plasmodium infection, which is linked to impaired ovarian development and immune activation. The transcriptome of mosGILTnull A. gambiae was therefore compared to wild type (WT) by RNA-sequencing to delineate mosGILT-dependent pathways. Compared to WT mosquitoes, mosGILTnull A. gambiae demonstrated altered expression of genes related to oogenesis, 20-hydroxyecdysone synthesis, as well as immune-related genes. Serendipitously, the zero population growth gene, zpg, an essential regulator of germ cell development was found to be one of the most downregulated genes in mosGILTnull mosquitoes. These results provide the crucial missing link between two previous studies on the role of zpg and mosGILT in ovarian development. This study further demonstrates that mosGILT has the potential to serve as a target for the biological control of mosquito vectors and to influence the Plasmodium life cycle within the vector.

genomics↗

bioRxiv2023

Metabolomic changes associated with acquired resistance to Ixodes scapularis

Guinea pigs repeatedly exposed to Ixodes scapularis develop acquired resistance to the ticks (ATR). The molecular mechanisms of ATR have not been fully elucidated, and partially involve immune responses to proteins in tick saliva. In this study, we examined the metabolome of sera of guinea pigs during the development of ATR. Induction of components of the tyrosine metabolic pathway, including hydroxyphenyllactic acid (HPLA), were associated with ATR. We therefore administered HPLA to mice, an animal that does not develop ATR, and exposed the animals to I. scapularis. We also administered nitisinone, a known inhibitor of tyrosine degradation, to another group of mice. The mortality of I. scapularis that fed on mice given HPLA or nitisinone was 26% and 72% respectively, compared with 2% mortality among ticks that fed on control animals. These data indicate that metabolic changes that occur after tick bites contribute to ATR.

biochemistry↗

bioRxiv2022

CD36 homologs determine microbial resistance to the Lyme disease spirochete

Pattern recognition receptors sense pathogens in arthropods and mammals through distinct immune processes. Whether these molecules share a similar function and recognize the same microbe in evolutionarily distant species remain ill-defined. Here, we establish that the CD36 superfamily is required for Borrelia burgdorferi resistance in both the arthropod vector and humans. Using the blacklegged tick Ixodes scapularis and an electronic health record-linked biobank, we demonstrate that CD36 members elicit immunity to the Lyme disease spirochete. In ticks, the CD36-like protein Croquemort recognizes lipids and initiates the immune deficiency and jun N-terminal kinase pathways against B. burgdorferi. In humans, exome sequencing and clinical information reveal that individuals with CD36 loss-of-function variants have increased prevalence of Lyme disease. Altogether, we discovered a conserved mechanism of anti-bacterial immunity. One Sentence SummaryLipid receptors belonging to the CD36 superfamily exhibit a shared immune function in both ticks and humans.

immunology↗

bioRxiv2021

The Lyme Disease agent co-opts adiponectin receptor-mediated signaling in its arthropod vector

Adiponectin-mediated pathways contribute to mammalian homeostasis; however, little is known about adiponectin and adiponectin receptor signaling in arthropods. In this study, we demonstrate that Ixodes scapularis ticks have an adiponectin receptor-like protein (ISARL) but lack adiponectin - suggesting activation by alternative pathways. ISARL expression is significantly upregulated in the tick gut after Borrelia burgdorferi infection suggesting that ISARL-signaling may be co-opted by the Lyme disease agent. Consistent with this, RNA interference (RNAi)-mediated silencing of ISARL significantly reduced the B. burgdorferi burden in the tick. RNA-seq-based transcriptomics and RNAi assays demonstrate that ISARL-mediated phospholipid metabolism by phosphatidylserine synthase I is associated with B. burgdorferi survival. Furthermore, the tick complement C1q-like protein 3 interacts with ISARL, and B. burgdorferi facilitates this process. This study identifies a new tick metabolic pathway that is connected to the life cycle of the Lyme disease spirochete. Significance StatementAdiponectin binds to adiponectin receptors and participates in glucose and lipid metabolism in mammals. In this study, we found that ticks have an adiponectin receptor-like protein but lack adiponectin. Importantly, we demonstrated that the Lyme disease agent, Borrelia burgdorferi, takes advantage of the adiponectin receptor signaling pathway to establish infection in its arthropod vector, Ixodes scapularis. Our study sheds light on the understanding of Borrelia-tick interactions and provides insights into how a human infectious disease agent may evolve to manipulate host metabolism for its own benefits. Understanding this pathway may lead to new ways to interfere with the Borrelia life cycle, and this mechanism may be applicable to additional microbes that are transmitted by ticks, mosquitoes or other arthropods.

microbiology↗

bioRxiv2021

UBXN3B Restricts Viral Pathogenesis by Maintaining Hematopoietic Homeostasis

Hematopoiesis is finely regulated to enable timely production of the right numbers and types of mature immune cells to maintain tissue homeostasis. Dysregulated hematopoiesis may compromise antiviral immunity and/or exacerbate immunopathogenesis. Herein, we report an essential role of UBXN3B in maintenance of hematopoietic homeostasis and restriction of immunopathogenesis during respiratory viral infection. Ubxn3b deficient (Ubxn3b-/-) mice are highly vulnerable to SARS-CoV-2 and influenza A infection, characterized by more severe lung immunopathology, lower virus-specific IgG, significantly fewer B cells, but more myeloid cells than Ubxn3b+/+ littermates. This aberrant immune compartmentalization is recapitulated in uninfected Ubxn3b-/- mice. Mechanistically, UBXN3B controls precursor B-I (pre-BI) transition to pre-BII and subsequent proliferation in a cell-intrinsic manner, by maintaining BLNK protein stability and pre-BCR signaling. These results reveal an essential role of UBXN3B for the early stage of B cell development.

immunology↗

bioRxiv2020

STING deficiency-associated aberrant CXCL10 expression contributes to pathogenesis of arthritogenic alphaviruses

Arthritogenic alphaviruses such as Chikungunya virus and Onyong nyong virus cause acute and chronic crippling arthralgia associated with inflammatory immune responses. However, the physiological functions of individual immune signaling pathways in the pathogenesis of alphaviral arthritis remain poorly understood. Here we report that a deficiency in the stimulator-of-interferon-genes (STING) led to enhanced viral loads, exacerbated inflammation and selectively elevated expression of CXCL10, a chemoattractant for monocytes/macrophages/T cells, in mouse feet. Cxcl10-/- mice had the same viremia as wild-type animals, but fewer immune infiltrates and lower viral loads in footpads at the peak of arthritic disease (6-8 days post infection). Macrophages constituted the largest immune cell population in footpads following infection, which were significantly reduced in Cxcl10-/- mice. The viral RNA loads in neutrophils and macrophages were reduced in Cxcl10-/- compared to wild-type mice. In summary, our results demonstrate that STING signaling represses, while CXCL10 signaling promotes, pathogenesis of alphaviral disease.

immunology↗

bioRxiv2020

Macrophage scavenger receptor 1 controls Chikungunya virus infection through autophagy

Macrophage scavenger receptor 1 (MSR1) mediates the endocytosis of modified low-density lipoproteins and plays an important antiviral role. However, the molecular mechanism underlying MSR1 antiviral actions remains elusive. Herein, we report that MSR1 activates autophagy to restrict infection of Chikungunya virus (CHIKV), an arthritogenic alphavirus that causes acute and chronic crippling arthralgia. Msr1 expression was rapidly upregulated after CHIKV infection in mice. Msr1 knockout mice had elevated viral loads and increased susceptibility to CHIKV arthritis along with a normal type I IFN response. Induction of LC3 lipidation by CHIKV, a marker of autophagy, was reduced in Msr1-/- cells. Mechanistically, MSR1 interacted with ATG12 through its cytoplasmic tail and this interaction was enhanced by CHIKV nsP1 protein. MSR1 repressed CHIKV replication through ATG5-ATG12-ATG16L1 and this was dependent on the FIP200-and-WIPI2-binding domain, but not the WD40 domain of ATG16L1. Our results elucidate an antiviral role for MSR1 involving the autophagic function of ATG5-ATG12-ATG16L1.

microbiology↗