impairs T cell priming by inducing dendritic cell death.

The lack of effective adaptive immunity against leads to chronic or repeated infection and serious disease sequelae. Dendritic cells (DCs) are professional antigen-presenting cells that are crucial for the activation of T cells during infection. cDC1s and cDC2s are the two main DC subsets responsible for T cell priming, but little is known about how affects their ability to prime T cells.

Cytotoxic CD4+ T Cells Are Induced during Infection with Chlamydia trachomatis.

Chlamydia trachomatis is the most common cause of bacterial sexually transmitted infection in both men and women. Immunity to C. trachomatis involves many cell types, but CD4+ T cells play a key role in protecting the host during natural infection.

The PD-1/PD-L1 pathway is induced during Borrelia burgdorferi infection and inhibits T cell joint infiltration without compromising bacterial clearance.

The Lyme disease bacterial pathogen, Borrelia burgdorferi, establishes a long-term infection inside its mammalian hosts. Despite the continued presence of the bacteria in animal models of disease, inflammation is transitory and resolves spontaneously. T cells with limited effector functions and the inability to become activated by antigen, termed exhausted T cells, are present in many long-term infections.

T cell responses to Chlamydia.

Chlamydia trachomatis is the most commonly reported sexually transmitted infection in the United States. The high prevalence of infection and lack of a vaccine indicate a critical knowledge gap surrounding the host's response to infection and how to effectively generate protective immunity. The immune response to C.

Sticholysins, pore-forming proteins from a marine anemone can induce maturation of dendritic cells through a TLR4 dependent-pathway.

Sticholysins (Sts) I and II (StI and StII) are pore-forming proteins (PFPs), purified from the Caribbean Sea anemone Stichodactyla helianthus. StII encapsulated into liposomes induces a robust antigen-specific cytotoxic CD8 T lymphocytes (CTL) response and in its free form the maturation of bone marrow-derived dendritic cells (BM-DCs). It is probable that the latter is partially supporting in part the immunomodulatory effect on the CTL response induced by StII-containing liposomes.

Antigen-specific memory and naïve CD4+ T cells following secondary Chlamydia trachomatis infection.

Memory antigen-specific CD4+ T cells against Chlamydia trachomatis are necessary for protection against secondary genital tract infection. While it is known that naïve antigen-specific CD4+ T cells can traffic to the genital tract in an antigen-specific manner, these T cells are not protective during primary infection. Here, we sought to compare the differences between memory and naïve antigen-specific CD4+ T cells in the same mouse following secondary infection using transgenic CD4+ T cells (NR1 T cells).

Gamma Interferon Is Required for Clearance but Is Dispensable for T Cell Homing to the Genital Tract.

While there is no effective vaccine against infection, previous work has demonstrated the importance of -specific CD4 T cells (NR1 T cells) in pathogen clearance. Specifically, NR1 T cells have been shown to be protective in mice, and this protection depends on the host's ability to sense the cytokine gamma interferon (IFN-γ). However, it is unclear what role NR1 production or sensing of IFN-γ plays in T cell homing to the genital tract or T cell-mediated protection against Using two-photon microscopy and flow cytometry, we found that naive wild-type (WT), IFN-γ, and IFN-γR NR1 T cells specifically home to sections in the genital tract that contain We also determined that protection against infection requires production of IFN-γ from either NR1 T cells or endogenous cells, further highlighting the importance of IFN-γ in clearing infection.

The well-evolved pathogen.

Stan Falkow looked at the world with his eyes peering from the outer membrane of a gram-negative bacterium. It was a great vantage point from which to dream about the possible superpowers these organisms might have. He mused about these dreams with his trainees who sometimes found through rigorous scientific exploration that the superpowers really were there! Stan also realized that bacterial pathogenesis by definition was a two-way street, and that masterful understanding of bacterial virulence factors also required a masterful understanding of host cell processes against which the virulence factors were deployed.

Gut-Innervating Nociceptor Neurons Regulate Peyer's Patch Microfold Cells and SFB Levels to Mediate Salmonella Host Defense.

Gut-innervating nociceptor sensory neurons respond to noxious stimuli by initiating protective responses including pain and inflammation; however, their role in enteric infections is unclear. Here, we find that nociceptor neurons critically mediate host defense against the bacterial pathogen Salmonella enterica serovar Typhimurium (STm). Dorsal root ganglia nociceptors protect against STm colonization, invasion, and dissemination from the gut.

Early Colonization of the Upper Genital Tract by Chlamydia muridarum Is Associated with Enhanced Inflammation Later in Infection.

is the most commonly reported bacterial sexually transmitted infection in the United States. Modeling infection in animals can be challenging, as mice naturally clear when it is deposited in the lower genital tract. However, can productively infect mice when the lower genital tract is bypassed and bacteria are deposited directly into the upper genital tract via transcervical inoculation.

A Chlamydia trachomatis Strain Expressing Ovalbumin Stimulates an Antigen-Specific CD4 T Cell Response in Mice.

Antigen-specific CD4 T cells against are crucial for driving bacterial clearance and mediating protection against reinfection. Although the protein Cta1 has been identified to be a dominant murine CD4 T cell antigen, its level of expression during the bacterial developmental cycle and precise localization within the host cell are unknown. Newly developed tools for genetic manipulation have allowed us to generate a strain expressing a heterologous CD4 T cell epitope from ovalbumin (OVA) consisting of OVA residues 323 to 339 (OVA).

A FACS-Based Genome-wide CRISPR Screen Reveals a Requirement for COPI in Chlamydia trachomatis Invasion.

The invasion of Chlamydia trachomatis, an obligate intracellular bacterium, into epithelial cells is driven by a complex interplay of host and bacterial factors. To comprehensively define the host genes required for pathogen invasion, we undertook a fluorescence-activated cell sorting (FACS)-based CRISPR screen in human cells. A genome-wide loss-of-function library was infected with fluorescent C.

The Vacuolar Pathway in Macrophages Plays a Major Role in Antigen Cross-Presentation Induced by the Pore-Forming Protein Sticholysin II Encapsulated Into Liposomes.

Cross-presentation is an important mechanism for the differentiation of effector cytotoxic T lymphocytes (CTL) from naïve CD8 T-cells, a key response for the clearance of intracellular pathogens and tumors. The liposomal co-encapsulation of the pore-forming protein sticholysin II (StII) with ovalbumin (OVA) (Lp/OVA/StII) induces a powerful OVA-specific CTL activation and an anti-tumor response . However, the pathway through which the StII contained in this preparation is able to induce antigen cross-presentation and the type of professional antigen presenting cells (APCs) involved have not been elucidated.

Action Needed on Chlamydia Vaccines.

Chlamydia trachomatis is the most common infectious disease in the USA for which the Centers for Disease Control (CDC) collects case reports. Its prevalence in young women is a public health crisis given the threat to their reproductive health. Consequently, development of a vaccine to prevent infection should be prioritized.

LysMD3 is a type II membrane protein without an role in the response to a range of pathogens.

Germline-encoded receptors recognizing common pathogen-associated molecular patterns are a central element of the innate immune system and play an important role in shaping the host response to infection. Many of the innate immune molecules central to these signaling pathways are evolutionarily conserved. LysMD3 is a novel molecule containing a putative peptidoglycan-binding domain that has orthologs in humans, mice, zebrafish, flies, and worms.

Pathology after infection is driven by nonprotective immune cells that are distinct from protective populations.

Infection with drives severe mucosal immunopathology; however, the immune responses that are required for mediating pathology vs. protection are not well understood. Here, we employed a mouse model to identify immune responses required for -induced upper genital tract pathology and to determine whether these responses are also required for bacterial clearance.

An Excess of the Proinflammatory Cytokines IFN-γ and IL-12 Impairs the Development of the Memory CD8+ T Cell Response to Chlamydia trachomatis.

The obligate intracellular bacterium Chlamydia trachomatis is the most common cause of bacterial sexually transmitted disease in the United States and the leading cause of preventable blindness worldwide. Transfer of cultured Chlamydia-specific CD8(+) T cells or vaccination with recombinant virus expressing an MHC I-restricted Chlamydia Ag confers protection, yet surprisingly a protective CD8(+) T cell response is not stimulated following natural infection. In this study, we demonstrate that the presence of excess IL-12 and IFN-γ contributes to poor memory CD8(+) T cell development during C.

Global Mapping of the Inc-Human Interactome Reveals that Retromer Restricts Chlamydia Infection.

Chlamydia trachomatis is a leading cause of genital and ocular infections for which no vaccine exists. Upon entry into host cells, C. trachomatis resides within a membrane-bound compartment—the inclusion—and secretes inclusion membrane proteins (Incs) that are thought to modulate the host-bacterium interface.

VACCINES. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells.

Genital Chlamydia trachomatis (Ct) infection induces protective immunity that depends on interferon-γ-producing CD4 T cells. By contrast, we report that mucosal exposure to ultraviolet light (UV)-inactivated Ct (UV-Ct) generated regulatory T cells that exacerbated subsequent Ct infection. We show that mucosal immunization with UV-Ct complexed with charge-switching synthetic adjuvant particles (cSAPs) elicited long-lived protection in conventional and humanized mice.

Cm-p5: an antifungal hydrophilic peptide derived from the coastal mollusk Cenchritis muricatus (Gastropoda: Littorinidae).

Antimicrobial peptides form part of the first line of defense against pathogens for many organisms. Current treatments for fungal infections are limited by drug toxicity and pathogen resistance. Cm-p5 (SRSELIVHQRLF), a peptide derived from the marine mollusk Cenchritis muricatus peptide Cm-p1, has a significantly increased fungistatic activity against pathogenic Candida albicans (minimal inhibitory concentration, 10 µg/ml; EC50, 1.

Protective immunity against Chlamydia trachomatis can engage both CD4+ and CD8+ T cells and bridge the respiratory and genital mucosae.

Understanding the cellular populations and mechanisms responsible for overcoming immune compartmentalization is valuable for designing vaccination strategies targeting distal mucosae. In this study, we show that the human pathogen Chlamydia trachomatis infects the murine respiratory and genital mucosae and that T cells, but not Abs, elicited through intranasal immunization can protect against a subsequent transcervical challenge. Unlike the genital infection where CD8(+) T cells are primed, yet fail to confer protection, we found that intranasal priming engages both CD4(+) and CD8(+) T cells, allowing for protection against genital infection with C.

Integrin α4β1 is necessary for CD4+ T cell-mediated protection against genital Chlamydia trachomatis infection.

Chlamydia trachomatis infection is the most common sexually transmitted bacterial infection in the United States and a significant health burden worldwide. Protection from Chlamydia infection in the genital mucosa is dependent on IFN-γ derived from CD4(+) Th1 cells. These CD4(+) T cells must home successfully to the genital tract to exert their effector function and decrease C.

Chlamydia trachomatis-induced alterations in the host cell proteome are required for intracellular growth.

Intracellular pathogens directly alter host cells in order to replicate and survive. While infection-induced changes in host transcription can be readily assessed, posttranscriptional alterations are more difficult to catalog. We applied the global protein stability (GPS) platform, which assesses protein stability based on relative changes in an adjoining fluorescent tag, to identify changes in the host proteome following infection with the obligate intracellular bacteria Chlamydia trachomatis.