Conserved molecular chaperone PrsA stimulates protective immunity against group A Streptococcus.

Group A Streptococcus (GAS) is a significant human pathogen that poses a global health concern. However, the development of a GAS vaccine has been challenging due to the multitude of diverse M-types and the risk of triggering cross-reactive immune responses. Our previous research has identified a critical role of PrsA1 and PrsA2, surface post-translational molecular chaperone proteins, in maintaining GAS proteome homeostasis and virulence traits.

Subunit vaccines with a saponin-based adjuvant boost humoral and cellular immunity to MERS coronavirus.

Middle East respiratory syndrome coronavirus (MERS-CoV) outbreaks have constituted a public health issue with drastic mortality higher than 34%, necessitating the development of an effective vaccine. During MERS-CoV infection, the trimeric spike protein on the viral envelope is primarily responsible for attachment to host cellular receptor, dipeptidyl peptidase 4 (DPP4). With the goal of generating a protein-based prophylactic, we designed a subunit vaccine comprising the recombinant S1 protein with a trimerization motif (S1-Fd) and examined its immunogenicity and protective immune responses in combination with various adjuvants.

The protective effect of cannabinoids against colorectal cancer cachexia through modulation of inflammation and immune responses.

Cancer cachexia is a multifactorial disorder characterized by weight loss and muscle wasting, and there are currently no FDA-approved medications. In the present study, upregulation of six cytokines was observed in serum samples from patients with colorectal cancer (CRC) and in mouse models. A negative correlation between the levels of the six cytokines and body mass index in CRC patients was seen.

Pre-Clinical Pregnancy Models for Evaluating Zika Vaccines.

Zika virus (ZIKV) infection during pregnancy can result in a variety of developmental abnormalities in the fetus, referred to as Congenital Zika Syndrome (CZS). The effects of CZS can range from the loss of the viable fetus to a variety of neurological defects in full-term infants, including microcephaly. The clinical importance of ZIKV-induced CZS has driven an intense effort to develop effective vaccines.

Pla Protein Thwarts T Cell Defense against Plague.

Plague is a rapidly lethal human disease caused by the bacterium This study demonstrated that the plasminogen activator Pla, a protease that promotes fibrin degradation, thwarts T cell-mediated defense against fully virulent Introducing a single point mutation into the active site of Pla suffices to render fully virulent susceptible to primed T cells. Mechanistic studies revealed essential roles for fibrin during T cell-mediated defense against Pla-mutant Moreover, the efficacy of T cell-mediated protection against various strains displayed an inverse relationship with their levels of Pla activity. Together, these data indicate that Pla functions to thwart fibrin-dependent T cell-mediated defense against plague.

Zika virus infection in immunocompetent pregnant mice causes fetal damage and placental pathology in the absence of fetal infection.

Zika virus (ZIKV) infection during human pregnancy may cause diverse and serious congenital defects in the developing fetus. Previous efforts to generate animal models of human ZIKV infection and clinical symptoms often involved manipulating mice to impair their Type I interferon (IFN) signaling, thereby allowing enhanced infection and vertical transmission of virus to the embryo. Here, we show that even pregnant mice competent to generate Type I IFN responses that can limit ZIKV infection nonetheless develop profound placental pathology and high frequency of fetal demise.

Challenges of Vaccine Development for Zika Virus.

The emergence of outbreaks of Zika virus (ZIKV) in Brazil in 2015 was associated with devastating effects on fetal development and prompted a world health emergency and multiple efforts to generate an effective vaccine against infection. There are now more than 40 vaccine candidates in preclinical development and six in clinical trials. Despite similarities with other flaviviruses to which successful vaccines have been developed, such as yellow fever virus and Japanese Encephalitis virus, there are unique challenges to the development and clinical trials of a vaccine for ZIKV.

TNFα and IFNγ but not perforin are critical for CD8 T cell-mediated protection against pulmonary Yersinia pestis infection.

Septic pneumonias resulting from bacterial infections of the lung are a leading cause of human death worldwide. Little is known about the capacity of CD8 T cell-mediated immunity to combat these infections and the types of effector functions that may be most effective. Pneumonic plague is an acutely lethal septic pneumonia caused by the Gram-negative bacterium Yersinia pestis.

Intranasal prophylaxis with CpG oligodeoxynucleotide can protect against Yersinia pestis infection.

Immunomodulatory agents potentially represent a new class of broad-spectrum antimicrobials. Here, we demonstrate that prophylaxis with immunomodulatory cytosine-phosphate-guanidine (CpG) oligodeoxynucleotide (ODN), a toll-like receptor 9 (TLR9) agonist, confers protection against Yersinia pestis, the etiologic agent of plague. The data establish that intranasal administration of CpG ODN 1 day prior to lethal pulmonary exposure to Y.

Fibrin facilitates both innate and T cell-mediated defense against Yersinia pestis.

The Gram-negative bacterium Yersinia pestis causes plague, a rapidly progressing and often fatal disease. The formation of fibrin at sites of Y. pestis infection supports innate host defense against plague, perhaps by providing a nondiffusible spatial cue that promotes the accumulation of inflammatory cells expressing fibrin-binding integrins.

Immunity to the conserved influenza nucleoprotein reduces susceptibility to secondary bacterial infections.

Influenza causes >250,000 deaths annually in the industrialized world, and bacterial infections frequently cause secondary illnesses during influenza outbreaks, including pneumonia, bronchitis, sinusitis, and otitis media. In this study, we demonstrate that cross-reactive immunity to mismatched influenza strains can reduce susceptibility to secondary bacterial infections, even though this fails to prevent influenza infection. Specifically, infecting mice with H3N2 influenza before challenging with mismatched H1N1 influenza reduces susceptibility to either Gram-positive Streptococcus pneumoniae or Gram-negative Klebsiella pneumoniae.

A protective epitope in type III effector YopE is a major CD8 T cell antigen during primary infection with Yersinia pseudotuberculosis.

Virulence in human-pathogenic Yersinia species is associated with a plasmid-encoded type III secretion system that translocates a set of Yop effector proteins into host cells. One effector, YopE, functions as a Rho GTPase-activating protein (GAP). In addition to acting as a virulence factor, YopE can function as a protective antigen.

Immunization with apoptotic phagocytes containing Histoplasma capsulatum activates functional CD8(+) T cells to protect against histoplasmosis.

We have previously revealed the protective role of CD8(+) T cells in host defense against Histoplasma capsulatum in animals with CD4(+) T cell deficiency and demonstrated that sensitized CD8(+) T cells are restimulated in vitro by dendritic cells that have ingested apoptotic macrophage-associated Histoplasma antigen. Here we show that immunization with apoptotic phagocytes containing heat-killed Histoplasma efficiently activated functional CD8(+) T cells whose contribution was equal to that of CD4(+) T cells in protection against Histoplasma challenge. Inhibition of macrophage apoptosis due to inducible nitric oxide synthase (iNOS) deficiency or by caspase inhibitor treatment dampened the CD8(+) T cell but not the CD4(+) T cell response to pulmonary Histoplasma infection.

Yersinia pestis YopE contains a dominant CD8 T cell epitope that confers protection in a mouse model of pneumonic plague.

Septic bacterial pneumonias are a major cause of death worldwide. Several of the highest priority bioterror concerns, including anthrax, tularemia, and plague, are caused by bacteria that acutely infect the lung. Bacterial resistance to multiple antibiotics is increasingly common.

IL-17 contributes to cell-mediated defense against pulmonary Yersinia pestis infection.

Pneumonic plague is one of the world's most deadly infectious diseases. The causative bacterium, Yersinia pestis, has the potential to be exploited as a biological weapon, and no vaccine is available. Vaccinating B cell-deficient mice with D27-pLpxL, a live attenuated Y.

TNFα and IFNγ contribute to F1/LcrV-targeted immune defense in mouse models of fully virulent pneumonic plague.

Immunization with the Yersinia pestis F1 and LcrV proteins improves survival in mouse and non-human primate models of pneumonic plague. F1- and LcrV-specific antibodies contribute to protection, however, the mechanisms of antibody-mediated defense are incompletely understood and serum antibody titers do not suffice as quantitative correlates of protection. Previously we demonstrated roles for tumor necrosis factor-alpha (TNFα) and gamma-interferon (IFNγ) during defense against conditionally attenuated pigmentation (pgm) locus-negative Y.

Distinct roles of complement receptor 3, Dectin-1, and sialic acids in murine macrophage interaction with Histoplasma yeast.

The yeast cells of dimorphic fungal pathogen Histoplasma reside primarily within the macrophages of an infected host; the interaction between the yeast and macrophage has a profound impact on host defense against the fungus. We used blocking antibodies and saccharides to identify the receptors that participate in the phagocytosis of and the cytokine response to Histoplasma. The phagocytosis and cytokine response results show that sialic acids on the macrophages were involved in the interaction between macrophages and Histoplasma.

D27-pLpxL, an avirulent strain of Yersinia pestis, primes T cells that protect against pneumonic plague.

Vaccinating with live, conditionally attenuated, pigmentation (Pgm)-deficient Yersinia pestis primes T cells that protect mice against pneumonic plague. However, Pgm-deficient strains are not considered safe for human use because they retain substantial virulence in animal models. Y.

Dendritic cells cross-present exogenous fungal antigens to stimulate a protective CD8 T cell response in infection by Histoplasma capsulatum.

The contribution of CD8 T cells in host defense against histoplasmosis is minor in the CD4 T cell-intact mouse, as it has been shown that depleting CD8 T cells only marginally affects fungal clearance. However, it remains to be determined whether the CD8 T cells are protective in a host lacking functional CD4 T cells. In this study, MHC class II-deficient mice infected with Histoplasma capsulatum (Histoplasma) kept the fungus in check for up to 16 wk, indicating that CD8 T cells are able to limit fungal replication.

The combined effect of IL-4 and IL-10 suppresses the generation of, but does not change the polarity of, type-1 T cells in Histoplasma infection.

Dominant type-1 cytokine production is induced in a murine model of systemic histoplasmosis. We used this model to investigate whether the presence of antagonistic cytokines during T cell priming changes the polarity of T cells in response to Histoplasma infection. Before infection with Histoplasma capsulatum, mice were injected twice with goat anti-mouse IgD antiserum (GalphaMdelta), which induced expression of dominant type-2 cytokines.

Functional T cells in primary immune response to histoplasmosis.

Functional T cells are critical to host defense against infection. It has been reported that functional T cells as determined by their cytokine production represent antigen-specific T cells in infectious disease models. In this study, we enumerated Histoplasma-specific interferon gamma-producing cells in bulk splenocyte culture and showed that infection with Histoplasma capsulatum, an intracellular pathogen of the macrophage, activated both CD4 and CD8 T cells.