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The causative agent of plague, Yersinia pestis, uses a type III secretion system to selectively destroy immune cells in humans, thus enabling Y. pestis to reproduce in the bloodstream and be transmitted to new hosts through fleabites. The host factors that are responsible for the selective destruction of immune cells by plague bacteria are unknown. Here we show that LcrV, the needle cap protein of the Y. pestis type III secretion system, binds to the 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, Fpr1-deficient mice have increased survival and antibody responses that are protective against plague. We identified FPR1.sup.R190W as a candidate resistance allele in humans that protects neutrophils from destruction by the Y. pestis type III secretion system. Thus, FPR1 is a plague receptor on immune cells in both humans and mice, and its absence or mutation provides protection against Y. pestis. Furthermore, plague selection of FPR1 alleles appears to have shaped human immune responses towards other infectious diseases and malignant neoplasms. The receptor FPR1 on human immune cells interacts with Yersinia pestis, mutations in this receptor provide resistance against plague in humans and Fpr1 deficiency enhances survival in mice., Author(s): Patrick Osei-Owusu [sup.1] [sup.2] , Thomas M. Charlton [sup.1] [sup.2] , Hwan Keun Kim [sup.1] [sup.2] , Dominique Missiakas [sup.1] [sup.2] , Olaf Schneewind [sup.1] [sup.2] Author Affiliations: (1) [...]

Peripheral sensitization is one of the primary mechanisms underlying the pathogenesis of chronic pain. However, candidate molecules involved in peripheral sensitization remain incompletely understood. We have shown that store-operated calcium channels (SOCs) are expressed in the dorsal root ganglion (DRG) neurons. Whether SOCs contribute to peripheral sensitization associated with chronic inflammatory pain is elusive. Here we report that global or conditional deletion of Orai1 attenuates Complete Freund's adjuvant (CFA)-induced pain hypersensitivity in both male and female mice. To further establish the role of Orai1 in inflammatory pain, we performed calcium imaging and patch-clamp recordings in wild-type (WT) and Orai1 knockout (KO) DRG neurons. We found that SOC function was significantly enhanced in WT but not in Orai1 KO DRG neurons from CFA- and carrageenan-injected mice. Interestingly, the Orai1 protein level in L3/4 DRGs was not altered under inflammatory conditions. To understand how Orai1 is modulated under inflammatory pain conditions, prostaglandin E2 (PGE2) was used to sensitize DRG neurons. PGE2-induced increase in neuronal excitability and pain hypersensitivity was significantly reduced in Orai1 KO mice. PGE2-induced potentiation of SOC entry (SOCE) was observed in WT, but not in Orai1 KO DRG neurons. This effect was attenuated by a PGE2 receptor 1 (EP1) antagonist and mimicked by an EP1 agonist. Inhibition of Gq/11, PKC, or ERK abolished PGE2- induced SOCE increase, indicating PGE2-induced SOCE enhancement is mediated by EP1-mediated downstream cascade. These findings demonstrate that Orai1 plays an important role in peripheral sensitization. Our study also provides new insight into molecular mechanisms underlying PGE2-induced modulation of inflammatory pain. [ABSTRACT FROM AUTHOR]

Renal dysfunction is a hallmark of spinal cord injury (SCI). Several SCI sequalae are implicated; however, the exact pathogenic mechanism of renal dysfunction is unclear. Herein, we found that T3 (T3Tx) or T10 (T10Tx) complete thoracic spinal cord transection induced hypotension, bradycardia, and hypothermia immediately after injury. T3Tx-induced hypotension but not bradycardia or hypothermia slowly recovered to levels in T10Tx SCI and uninjured mice -16 h after injury as determined by continuous radiotelemetry monitoring. Both types of thoracic SCI led to a marked decrease in albuminuria and proteinuria in all phases of SCI, whereas the kidney injury marker neutrophil gelatinase-associated lipocalin rapidly increased in the acute phase, remaining elevated in the chronic phase of T3Tx SCI. Renal interstitial and vascular elastin fragmentation after SCI were worsened during chronic T3Tx SCI. In the chronic phase, renal vascular resistance response to a step increase in renal perfusion pressure or a bolus injection of angiotensin II or norepinephrine was almost completely abolished after T3Tx SCI. Bulk RNA-sequencing analysis showed enrichment of genes involved in extracellular matrix remodeling and chemokine signaling in the kidney from T3Tx SCI mice. The serum level of interleukin-6 was elevated in the acute but not chronic phase of T3Tx and T10Tx SCI, whereas the serum amyloid A1 level was elevated in both acute and chronic phases. We conclude that tissue fibrosis and hemodynamic impairment are involved in renal dysfunction resulting from thoracic SCI; these pathological alterations, exacerbated by high thoracic-level injury, is mediated at least partly by renal microvascular extracellular matrix remodeling. [ABSTRACT FROM AUTHOR]

5-[HT.sub.1A]-receptor agonists rapidly restore blood pressure and sympathetic activity in conscious rats subjected to hypotensive hemorrhage. 5-[HT.sub.1A]-receptor activation has also been shown to produce a robust increase in baroreceptor-dependent, pulse-synchronous firing of cardiac sympathetic nerves in anesthetized cats. To determine whether 5-[HT.sub.1A]-receptor agonists reverse hemorrhage-induced suppression of sympathetic activity through facilitation of the arterial baroreflex, the effects of the 5-[HT.sub.1A]-receptor agonist, 8-OH-DPAT, were assessed in male Sprague-Dawley rats subjected to sinoaortic baroreceptor denervation and subsequent hypotensive hemorrhage. 8-OH-DPAT produced rapid pressor and sympathoexcitatory responses in hemorrhaged animals that were attenuated, but not blocked, by sinoaortic denervation (SAD) (+49 [+ or -] 4 vs. +37 [+ or -] 4 mmHg; +165 [+ or -] 30 vs. +92 [+ or -] 24% baseline, P < 0.01). Spectral analysis of sympathetic activity showed that SAD abolished the 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT)-mediated increases in pulse-synchronous (13 [+ or -] 1 vs. 5 [+ or -] 1% total power for intact vs. SAD rats, P < 0.01) and Mayer wave-related bursting (18 [+ or -] 3 vs. 8 [+ or -] 1% total power, P < 0.05). However, 8-OH-DPAT continued to increase total power (+72 [+ or -] 22 vs. -63 [+ or -] 7% prehemorrhage total power, P < 0.05) and power at the respiratory frequency (35 [+ or -] 2 vs. 25 [+ or -] 4% total power) in SAD animals. These data indicate that full expression of the sympathoexcitatory effect of 8-OH-DPAT requires a functional arterial baroreflex. However, a portion of the effect is due to activation of arterial baroreflexindependent sympathetic pathways. spectral analysis; 8-hydroxy-2-(di-n-propylamino)-tetralin; Mayer wave; respiration