FPR1 is the plague receptor on host immune cells

Abstract

The plague agent, Yersinia pestis, employs a type III secretion system (T3SS) to selectively destroy human immune cells, thereby enabling its replication in the bloodstream and transmission to new hosts via fleabite. The host factors responsible for the selective destruction of immune cells by plague bacteria were not known. Here we show that LcrV, the needle cap protein of the Y. pestis T3SS, binds N-formylpeptide receptor (FPR1) on human immune cells to promote the translocation of bacterial effectors. Plague infection in mice is characterized by high mortality, however N-formylpeptide receptor deficient animals exhibit increased survival and plagueprotective antibody responses. We identified FPR1 p.R190W as a candidate human resistance allele that protects neutrophils from Y. pestis T3SS. These findings reveal the plague receptor on immune cells and show that FPR1 mutations provide for plague survival, which appears to have shaped human immune responses towards other infectious diseases and malignant neoplasms.Yersinia pestis has caused human disease for more than 5,000 years 1 . Three pandemics were recorded, including the plague of Justinian (6 th -8 th ), the Black Death (14 th -18 th ) and the Asian Pandemic (19 th -20 th century) 2 . The Black Death killed more than half of Europe's population, suggesting plague must have shaped the human immune system by selecting for mutations that confer resistance 3 . Carriers of CCR5-Δ32, a gene variant of CC-type chemokine receptor 5 (CCR5), are resistant to infections with human immunodeficiency virus type 1 4 . CCR5 is a member of the 7-transmembrane spanning G protein coupled receptor (GPCR) family that is expressed on immune cells, whereas CCR5-Δ32 is not presented on cell surfaces 5 . The allele frequency of CCR5-Δ32 is high in Northern Europe and originated 800 years ago, suggesting its selection may be linked to the Black Death 6 . However, studies in mice did not reveal an impact of CCR5 on plague survival 7,8 . Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Correspondence should be addressed to D.M.

Yersinia pseudotuberculosis YopH targets SKAP2-dependent and independent signaling pathways to block neutrophil antimicrobial mechanisms during infection

“…So our findings that YopH is critical to block ROS production support the idea that YopH may also block NETosis observed after infection of human neutrophils with a TT3S-minus strain but not WT Yptb strain [88]. We also found that degranulation was not dependent on SKAP2 after integrin and GPCR activation, receptors triggered by Yersinia [18,19,[22][23][24][25]. Thus, degranulation could contribute to the partial elimination of the ΔyopH mutant observed in tissue infection of the Skap2KO mice (Fig 2A), because YopH was sufficient to reduce MMP-9 release from all three receptors tested (Fig 6A-6C).…”

“…Since ΔyopH growth was restored in gp91 phox-/mice we evaluated the ability of YopH to block ROS production downstream of three major receptor classes (integrin receptors, G-protein coupled receptor (GPCR) and FcγR) known to activate the NADPH oxidase complex, two of which may be stimulated during Yptb infection [18,19,[22][23][24][25]. BM WT neutrophils were infected with WT-Yptb, ΔyopH, Δ5, or Δ5+pYopH and stimulated with poly-RGD (a polymer of arginine-glutamate-aspartate) to trigger integrin receptors, primed with E. coli lipopolysaccharide (LPS) and then stimulated with formyl-methionyl-leucyl-phenylalanine (fMLP) to trigger GPCR, or stimulated with IgG immune complex (IC) to trigger Fcγ receptor (FcγR) ( Fig 3A-3C) [49,55,[71][72][73][74][75][76].…”

“…This binding facilitates Yop-injection into neutrophils during tissue infection, whereas in the absence of Yops, the binding via these adhesins triggers phagocytosis of Yptb [15,20,21]. In addition to integrin receptor-mediated interactions, Yersinia activates other receptors on neutrophils during infection, including G-protein coupled receptors (GPCRs) [22][23][24][25]. Activation of integrin receptors and GPCRs in turn leads to a variety of neutrophil antimicrobial responses including reactive oxygen species (ROS) production and proteolytic enzyme release from granule stores, also known as degranulation.…”

The ambiguous role of FPR1 in immunity and inflammation

“…For example, Fpr1 −/mice are protected against infection by Yersinia pestis, in line with the discovery that FPR1 acts as the receptor for this pathogen, which is the causative agent of human plague. 9 Moreover, Fpr1 −/mice subjected to ischemia-reperfusion damage to the heart present reduced inflammation, cardiomyocyte apoptosis and ventricular remodeling, accompanied by the inhibition of the mitogen-activated protein kinases (MAPK) pathway. 10 Similarly, FPR1 plays a negative role in celiac disease, a highly prevalent autoimmune disorder that can be attenuated but not cured by a gluten-free diet.…”

Techniques and Strategies for Potential Protein Target Discovery and Active Pharmaceutical Molecule Screening in a Pandemic

“…At the same time, the use of FPR1 inhibitors such as mAb can enhance the immune response and alleviate infection, indicating that FPR1 plays an important role in viral pathogenesis. 67 Recently, Yang et al 68 found that Yersinia pestis invaded CHO-SIGNR1, but did not infect other CHO transducers, indicating that SIGNR1 (CD209b) is the core lipopolysaccharide receptor of Yersinia pestis . In order to verify the specificity of the interaction between Yersinia pestis and SIGNR1, the team further proved that SIGNR1 antibody, mannan, His-Mermaid, and CD66 can inhibit core LPS-SIGNR1 interaction.…”