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  • br FPRs regulate anti microbial

    2022-01-20


    FPRs regulate anti-microbial responses The classic evidence supporting FPR as an anti-microbial receptor is that bacteria are the major biological source of chemotactic formyl peptides, fMLF binds to FPR and fMLF activates chemotactic and anti-microbial responses in neutrophils 2., 3.. Recently, Hp(2–20), a non-formylated peptide fragment produced by Helicobacter pylori, was reported to be an agonist at FPRL1 and FPRL2 [19]. In vivo evidence for the involvement of murine FPR1 in anti-bacterial host defense is provided by the increased susceptibility of FPR1−/− mice to infection with Listeria monocytogenes[9]. In unstressed conditions, these mice appear normal, indicating that FPR1 could be a dispensable gene. Neutrophil responses to relatively low doses of fMLF were absent in mFPR1−/− mice. Although this result is suggestive, additional challenges with other types of bacteria will be needed to assess the general importance of FPR to anti-bacterial host defense. The requirement of proper neutrophil function triggered by fMLF in anti-microbial defense is suggested also by the reduced resistance to bacterial challenge associated with the absence of CD38 [27]. In humans, dysfunctional variant FPR AACOCF3 F110S and C126W are associated with localized juvenile periodonitis (LJP) [28]. Consistent with a direct causal role in this disease, these variants exhibit severe or complete deficiency in Gi coupling in transfected cells [29]. Primary neutrophils obtained from LJP patients of unknown FPR genotype bind fMLF poorly and have reduced chemotaxis in response to fMLF 30., 31.. Thus, FPR in human neutrophils might have an important role in host defense against Actinobacillus actinomycetescomitans, a bacterial strain responsible for LJP. However, additional confirmatory cohort studies and analysis of primary neutrophils from individuals carrying the defective alleles are needed to validate this. It is puzzling that severe defects in Gi protein coupling by mutated FPRs are associated with only a localized microbial infection, not with a generally increased susceptibility to other infectious diseases. One possible explanation is that other related receptors could compensate for the loss of FPR function to a certain degree. During an anti-bacterial response, phagocytic cells could be attracted not only by chemotactic peptides produced by invading microorganisms, but also by host-derived anti-bacterial peptides, one of which, LL37, acts, in part, by interacting with FPRL1 [32]. LL37 is a 37 amino-acid peptide naturally cleaved from the C-terminus of the anti-microbial protein cathelicidin, which is present in human neutrophil granules and epithelial cell surfaces. LL-37 is microbicidal, neutralizes endotoxin by direct binding and, in addition, has chemotactic activity for human neutrophils, monocytes, and resting T cells [32]. Therefore, LL37 could act to amplify the innate immune response. FPRs have also been implicated in host responses during HIV-1 infection because several synthetic peptides corresponding to amino-acid sequences of HIV-1 envelope proteins gp41 and gp120 are chemotactic agonists for FPR and/or FPRL1 (reviewed in [8]) (Table 1). Whether these peptide fragments are generated in vivo during proteolysis of envelope proteins shed by infecting virus or not is unclear. Also, whether the interaction of FPRs with HIV-1 envelope peptides, if it occurs in vivo, could mobilize the innate defense, thus favoring host resistance to HIV, or by contrast, provide signals promoting HIV-1 replication, requires further investigation. However, activation of FPR or FPRL1 by agonist peptides can desensitize two key HIV-1 coreceptors, CCR5 and CXCR4, and interfere with their coreceptor activity [8]. This property has potential as a novel anti-retroviral strategy. A synthetic gp41 peptide T20 (DP178), which activates FPR, has potent anti-HIV-1 activity in vitro[33], presumably by interfering with the conversion of gp41 in HIV-1 to a fusogenic competent configuration. T20 has been tested in clinical trials and significantly reduces viral load in AIDS patients [34]. However, whether activation of FPR by T20 and consequent downregulation of chemokine receptors in leukocytes contributes to its anti-HIV-1 activity in vivo is unknown.