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Immunity to Histoplasma capsulatum is dependent on a Th1 response. Infected CCR2−/− mice manifest exaggerated production of interleukin-4 in lungs and succumb to infection in conjunction with a paucity of dendritic cells. Szymczak and Deepe (p. 2125-2137) report that adoptive transfer of antigen-presenting dendritic cells suppressed interleukin-4 in CCR2−/− mice but did not improve fungal burden. The latter was achieved when CD4+ T cells were depleted of dendritic cell recipients. Thus, CD4+ T cells exert a deleterious impact on immunity in CCR2−/− mice. The presence of these inhibitory T cells may be facilitated by poor recruitment of dendritic cells.
Nutrient limitations in bacteria provoke the stringent response by the synthesis of (p)ppGpp. Geiger et al. (p. 1873-1883) show that in Staphylococcus aureus the synthase activity of the essential (p)ppGpp synthase/hydrolase RSH, a RelA/SpoT homolog, is dispensable for bacterial growth in vitro. The survival of mutants with a defective synthase domain is impaired after amino acid deprivation and virulence is attenuated in an abscess model of infection. The virulence of an rsh synthase mutant could be restored by compensatory mutation of the repressor codY. Thus, stringent conditions exerted in vivo lead to the derepression of CodY-regulated genes, which is required for full virulence.
Fic family proteins of Histophilus somni and Vibrio parahaemolyticus inactivate Rho GTPases, causing cytoskeletal disruption. The bovine pathogen H. somni causes pneumonia, with progression to septicemia. Zekarias et al. (p. 1850-1858) show that H. somni IbpA DR2/Fic adenylylates Rho GTPases in primary bovine alveolar epithelial cells, causing cell retraction and allowing paracellular passage of H. somni across the alveolar barrier. This result suggests a mechanism for invasion and septicemia. IbpA DR2/Fic antibody or convalescent-phase serum neutralized cytotoxicity and paracellular migration. This parallels passive antibody protection against H. somni pneumonia in the natural host and confirms the role of IbpA DR2/Fic in pathogenesis.
We understand little about how tick-borne relapsing fever Borrelia can evade innate immunity. Schott et al. (p. 2199-2208) identified an outer surface lipoprotein of B. parkeri that interacts with human complement regulators (factor H [CFH] and factor H-related protein 1 [CFHR-1]) and, simultaneously, the serum protease plasminogen. In contrast, B. turicatae did not bind complement regulators. Furthermore, B. parkeri is protected from complement-mediated killing, suggesting that CFH and plasminogen binding is relevant to the pathogenesis of relapsing fever spirochetes and may influence tissue tropism and immune evasion during natural infection in humans.
Certain intracellular pathogens exploit host signaling and trafficking pathways by targeting Rab GTPases and phosphoinositide metabolism. Moorhead et al. (p. 1990-2007) demonstrate that Chlamydia species target the host enzymes OCRL1 and PI4KIIα, which produce phosphatidylinositol-4-phosphate (PI4P), and Arf1, which facilitates Golgi complex recruitment of phosphatidylinositol-OH(4)-kinase (PI4K)- and PI4P-binding proteins. Furthermore, they show that the chlamydial inclusion is decorated with PI4P. Knockdown of OCRL1, PI4KIIα, and Arf1 mRNA dramatically decreases chlamydial development. These findings suggest that exploitation of phosphatidylinositol metabolism by chlamydiae is essential for chlamydial development.
A variety of Gram-negative bacteria, including Bordetella pertussis, are able to alter the molecular structure of lipid A in an environment-dependent manner, often resulting in modulated innate immune responses. Marr et al. (p. 2060-2069) show that substitution of the lipid A phosphate groups of B. pertussis lipooligosaccharide with glucosamine is required for the robust induction of Toll-like receptor 4 (TLR4)-mediated NF-κB activation and the release of proinflammatory cytokines when recognized by the human TLR4-MD-2-CD14 receptor. The murine counterpart, however, is much less discriminatory. With murine TLR4-MD-2-CD14, robust NF-κB activation and proinflammatory cytokine production are induced regardless of whether the B. pertussis endotoxin bears this glucosamine modification.
Infection by multiple organisms is a challenge for host immune defense as well as for diagnosis. Lundqvist et al. (p. 1924-1930) use a novel mouse model to show that malaria and relapsing fever coinfection, common in Africa, causes a dominant Th1 immunological profile, resulting in suppressed malaria but escalating Borrelia duttonii infection with severe anemia and a high fatality rate. In addition, the malaria infection successfully reactivates a dormant Borrelia infection in the brain, giving an important clue to the epidemiology of Borrelia. Their work reveals unexpected interactions between two tropical pathogens and calls for awareness in countries in which malaria is endemic.
Though recent reports have identified several factors that regulate genes within the Francisella pathogenicity island (FPI), how these proteins work in concert is poorly understood. Bell et al. (p. 2189-2198) describe that orphan two-component regulatory system (TCRS) members PmrA and KdpD form a functional TCRS. PmrA promoter binding and phosphorylation at Asp51 are important for effective FPI regulation, intramacrophage survival, and virulence. Additionally, PmrA interacts with FPI regulators MglA and SspA, which themselves bind to RNA polymerase. Thus, this work contributes to our growing understanding of Francisella virulence gene regulation.
Like many intracytoplasmic pathogens, spotted fever group Rickettsia species utilize actin-based motility for intracellular spread and dissemination to adjacent cells. Kleba et al. (p. 2240-2247) describe a transposon mutant of R. rickettsii with a small-plaque phenotype associated with a defect in actin tail formation. The mutation occurred within Sca2, a member of a family of autotransporter proteins. The Sca2 mutant displayed reduced virulence in a guinea pig model of infection and thus is a virulence factor for spotted fever group rickettsiae. The discovery of Sca2 provides an opportunity to identify and characterize host and bacterial proteins involved in assembling rickettsial actin tails.
The T-helper immune response is the critical host factor for susceptibility to Candida infection. The transcription factor GATA-3 is known as the master regulator of Th2 cell differentiation. Haraguchi et al. (p. 2302-2311) demonstrate that mice overexpressing GATA-3 are highly susceptible to systemic Candida infection. Overexpression of GATA-3 may impair macrophage antifungal activity by reducing the production of gamma interferon in response to Candida infection. Thus, GATA-3 is an important host factor in the regulation of susceptibility to disseminated candidiasis.