Relative contributions of myeloperoxidase and NADPH-oxidase to the early host defense against pulmonary infections with Candida albicans and Aspergillus fumigatus.

Generation of oxidative products by phagocytic cells is known to be an important host defense mechanism directed toward killing of invading microorganisms. The importance of two major oxidant-producing enzymes, myeloperoxidase (MPO) and NADPH-oxidase, in in vivo fungicidal action was directly compared in genetically engineered mice. Both MPO-deficient (MPO-/-) and NADPH-oxidase-deficient (X-linked chronic granulomatous disease [X-CGD]) mice showed increased susceptibility to pulmonary infections with Candida albicans and Aspergillus fumigatus compared with normal mice, and the X-CGD mice exhibited shorter survivals than MPO-/- mice. This increased mortality of X-CGD mice was associated with a 10- to 100-fold increased outgrowth of the fungi in their organs during the first 6 days. These results suggest that superoxide (O2-) produced by NADPH-oxidase is more important than hypochlorous acid (HOCl) produced by MPO, although both oxidative products obviously contribute to the host defense against pulmonary infection with those fungi. We also observed that MPO-/-/X-CGD double knockout mice showed comparable levels of susceptibility to the X-CGD mice against C. albicans and A. funigatus, indicating that MPO is unable to play a role in host defense in the absence of NADPH-oxidase. This strongly suggests that hydrogen peroxide, the precursor of HOCl, is solely derived from O2- produced by NADPH-oxidase.     

Role of myeloperoxidase in the host defense against fungal infection]

Neutrophils are believed to be the first line of defense against invading microorganisms, but in vivo roles of reactive oxygens produced by neutrophils are not well known. Myeloperoxidase (MPO) catalyzes reaction of hydrogen peroxide with chloride ion to produce hypochlorous acid that is used for microbial killing by phagocytic cells. To define the in vivo role of MPO, we generated mice having no peroxidase activity in their neutrophils or monocytes. MPO-deficient (MPO-KO) mice showed severely reduced cytotoxicity to Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, and other microorganisms, demonstrating that an MPO-dependent oxidative system is important for host defense against fungi. However, the significance of MPO compared to the NADPH-oxidase is still unclear because individuals with MPO deficiency are usually healthy in contrast to patients with chronic granulomatous disease (CGD) who present clinical symptoms early in life. To better understand the contributions of MPO and NADPH-oxidase to antifungal defense mechanisms, we compared the susceptibility of MPO-KO mice and CGD mice to infections by C. albicans. Interestingly, at the highest dose, the mortality of MPO-KO mice was comparable to CGD mice, but was the same as normal mice at the lowest dose. These results suggest that MPO and NADPH-oxidase are equally important for early host defense against a large inocula of Candida. Our present results suggest that MPO-deficient individuals could exhibit similar problems as CGD patients if exposed to a large number of microorganisms.     

Role of neutrophil-derived reactive oxygen species for host defense and inflammation

Neutrophil accumulation is a critical event in the pathogenesis of inflammation. The generation of hypochlorous acid by myeloperoxidase (MPO) in neutrophils is crucial to the host defense response. MPO-deficient (MPO-KO) mice showed severely reduced cytotoxicity to Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans and other microorganisms, demonstrating that an MPO-dependent oxidative system is important for in vivo host defense against fungi. On the other hand, impaired reactive oxygen species (ROS) production by neutrophils has previously been shown to cause an abnormal inflammatory response. In the present study, we have found that MPO-KO mice exhibit more severe pulmonary inflammation than wild-type mice when challenged with an intranasal administration of zymosan. In addition to measuring the kinetics of neutrophil accumulation, we also measured the production of macrophage inflammatory protein-2 (MIP-2) in the lung, and we correlate the degree of neutrophil accumulation with the production of this mediator. Our results demonstrate that MPO regulates the production of MIP-2, which may modulate neutrophil accumulation during lung inflammation.     

Microbicidal activity of vascular peroxidase 1 in human plasma via generation of hypochlorous acid

Members of the heme peroxidase family play an important role in host defense. Myeloperoxidase (MPO) is expressed in phagocytes and is the only animal heme peroxidase previously reported to be capable of using chloride ion as a substrate to form the highly microbicidal species hypochlorous acid (HOCl) at neutral pH. Despite the potent bacterial killing activity of HOCl, individuals who fail to express MPO typically show only a modest increase in some fungal infections. This may point to the existence of redundant host defense mechanisms. Vascular peroxidase 1 (VPO1) is newly discovered member of the heme peroxidase family. VPO1 is expressed in cells of the cardiovascular system and is secreted into the bloodstream. In the present study, we investigate whether VPO1 is capable of generating HOCl and its role in host defense. Like MPO, VPO1 in the presence of H₂O₂ and chloride generates HOCl. VPO1-dependent HOCl generation was demonstrated by chlorination of taurine and tyrosine using mass spectrometry. In addition, the VPO1/H₂O₂/Cl⁻ system can cause the chlorination of monochlorodimedone and the oxidation of 5-thio-2-nitrobenzoic acid. Purified VPO1 and VPO1 in plasma mediate bacterial killing that is dependent on chloride and H₂O₂; killing is inhibited by peroxidase inhibitors and by the H₂O₂ scavenger catalase. In the presence of erythrocytes, bacterial killing by VPO1 is slightly reduced. Thus, VPO1, in addition to MPO, is the second member of the heme peroxidase family capable of generating HOCl under physiological conditions. VPO1 is likely to participate in host defense, with bactericidal activity mediated through the generation of HOCl.     

Gamma interferon is not essential in host defense against disseminated candidiasis in mice.

In vitro studies have suggested a role for interferon gamma (IFN-gamma) in host defense against disseminated candidiasis, but in vivo studies are inconclusive. We utilized homozygous IFN-gamma knockout (GKO) mice to determine if the cytokine is essential in host defense against this disease. Genotypes of mice were determined by PCR with specific primers for the normal or disrupted IFN-gamma gene. The GKO status of the mice was confirmed by an enzyme-linked immunosorbent assay, which showed no detectable IFN-gamma produced by their splenocytes stimulated by concanavalin A. To test the susceptibility of GKO mice to candidiasis, the animals were infected either intravenously (i.v.) or intragastrically (i.g.) with Candida albicans. GKO mice infected i.v. survived as long as wild-type (WT) mice and showed no difference in Candida CFU counts in liver, spleen, or kidneys compared to those for WT mice. When animals were given Candida i.g., at 3 h or at 10 or 21 days after infection, there was no dissemination of Candida to the lung, liver, spleen, or kidneys for either GKO or WT mice. There was no difference in Candida CFU counts recovered from the stomach or intestines between GKO and WT mice. Histological examination of the stomach cardial-atrium fold, where the fungus was located, showed that GKO mice did not have evidence of more tissue damage or fungal invasion than WT mice. Finally, the jejunum for both types of mice showed no evidence of tissue damage or fungal invasion. These studies indicate that IFN-gamma is not essential in host defense against C. albicans that originates from a mucosal site or that is given directly into the bloodstream in a mouse model.     

Normal host defense during systemic candidiasis in mannose receptor-deficient mice

Pathogen pattern recognition receptors (PRRs) recognize common structural and molecular motifs present on microbial surfaces and contribute to induction of innate immune responses. The mannose receptor (MR), a carbohydrate-binding receptor expressed on subsets of macrophages, is considered one such PRR. In vitro experiments have implicated the MR in phagocytosis of mannose-bearing microbes, including Candida albicans, and enhancement of antifungal response by macrophages. However, the significance of the MR's contribution to immune response during systemic C. albicans infection has never been directly demonstrated. Using MR-deficient mice in an in vivo infection experiment, we examined the role of the MR in immune response during disseminated candidiasis. MR(-/-) and wild-type control mice were challenged intraperitoneally with C. albicans, and the survival rates, tissue fungal burden, inflammatory cell recruitment, and specific antibody production after infection were evaluated. We found no significant difference in survival between the two mouse strains. MR(-/-) mice had higher average fungal burdens in some of the organs on days 7 and 21 but exhibited competence in inflammatory cell recruitment and antibody production. We also observed in vitro that MR(-/-) peritoneal cavity macrophages were equally capable of C. albicans uptake and that phagocytosis could be blocked with beta-glucan. We conclude that the MR is not required for the normal host defense during disseminated candidiasis or for the phagocytosis of C. albicans and that a beta-glucan receptor may be required for C. albicans phagocytosis.     

Local Production of Chemokines during Experimental Vaginal Candidiasis

Recurrent vulvovaginal candidiasis, caused by Candida albicans, is a significant problem in women of childbearing age. Although cell-mediated immunity (CMI) due to T cells and cytokines is the predominant host defense mechanism against C. albicans at mucosal tissue sites, host defense mechanisms against C. albicans at the vaginal mucosa are poorly understood. Based on an estrogen-dependent murine model of vaginal candidiasis, our data suggest that systemic CMI is ineffective against C. albicans vaginal infections. Thus, we have postulated that local immune mechanisms are critical for protection against infection. In the present study, the kinetic production of chemokines normally associated with the chemotaxis of T cells, macrophages (RANTES, MIP-1alpha, MCP-1), and polymorphonuclear neutrophils (MIP-2) was examined following intravaginal inoculation of C. albicans in estrogen-treated or untreated mice. Results showed significant increases in MCP-1 protein and mRNA in vaginal tissue of infected mice as early as 2 and 4 days postinoculation, respectively, that continued through a 21-day observation period, irrespective of estrogen status. No significant changes were observed with RANTES, MIP-1alpha, or MIP-2, although relatively high constitutive levels of RANTES mRNA and MIP-2 protein were observed. Furthermore, intravaginal immunoneutralization of MCP-1 with anti-MCP-1 antibodies resulted in a significant increase in vaginal fungal burden early during infection, suggesting that MCP-1 plays some role in reducing the fungal burden during vaginal infection. However, the lack of changes in leukocyte profiles in vaginal lavage fluids collected from infected versus uninfected mice suggests that MCP-1 functions to control vaginal C. albicans titers in a manner independent of cellular chemotactic activity.     

Protective role of D-amino acid oxidase against Staphylococcus aureus infection

D-Amino acid oxidase (DAO) is a hydrogen peroxide-generating enzyme that uses a D-amino acid as a substrate. We hypothesized that DAO may protect against bacterial infection, because hydrogen peroxide is one of the most important molecules in the antibacterial defense systems in mammals. We show here that DAO suppressed the growth of Staphylococcus aureus in a manner that depended on the concentration of DAO and D-amino acid in vitro. Addition of catalase abolished the bacteriostatic activity of DAO. Although DAO plus D-Ala showed less bactericidal activity, addition of myeloperoxidase (MPO) greatly enhanced the bactericidal activity of DAO. Furthermore, DAO was able to utilize bacterial lysate, which contains D-Ala derived from peptidoglycan; this could produce hydrogen peroxide with, in the presence of myeloperoxidase, formation of hypochlorous acid. This concerted reaction of DAO and MPO led to the bactericidal action. In vivo experiments showed that DAO(-/-) (mutant) mice were more susceptible to S. aureus infection than were DAO(+/+) (wild-type) mice. These results suggest that DAO, together with myeloperoxidase, may play an important role in antibacterial systems in mammals.     

Effects of systemic cell-mediated immunity on vaginal candidiasis in mice resistant and susceptible to Candida albicans infections.

Studies to date with CBA/J mice suggest a limited role for systemic cell-mediated immunity (CMI) against vaginal Candida albicans infections. The results of the present study show that preinduced Candida-specific systemic CMI was equally nonprotective against C. albicans vaginal infections in mice with high (BALB/cJ), low (DBA/2), or intermediate (CBA/J) resistance to C. albicans infections. Similarly, the locally acquired partial protection against a second C. albicans vaginal infection was equally observed with BALB/cJ, DBA/2, and CBA/J mice. These results indicate that observations made previously with CBA/J mice were not murine strain specific and provide additional support for the hypothesis that systemic CMI does not represent a dominant host defense mechanism at the vaginal mucosa.     

Comparison of immunosuppressive effects of cyclosporine A in a murine model of systemic candidiasis and of localized thrushlike lesions.

Candida albicans is an opportunistic human pathogen preferentially causing invasive and disseminated infection in patients with defective phagocytic defenses and serious mucocutaneous infection in patients with deficient T-cell function. Phagocytes appear to protect the host from fungal invasion even in the absence of adaptive immune mechanisms, while as-yet-undefined T-cell-dependent factors seem necessary for control of C. albicans on body surfaces. To study host defense mechanisms on body surfaces, we developed a new model of thrush in artificial pneumatized cysts in mice. Cyclosporine A, a relative selective suppressor of T-cell-mediated immunity and natural killer cell activity, promoted the formation of thrushlike lesions on cyst surfaces and impeded elimination of C. albicans from such lesions. As expected from the absence of an impairment of antimicrobial phagocytic activity, cyclosporine A had no effect on systemic candidiasis induced by intravenous inoculation. Surprisingly, athymic nude mice were not more susceptible to superficial candidiasis than control mice and were comparably affected by cyclosporine A. In contrast, beige mice, which in addition to phagocytic dysfunction have reduced natural killer cell activity, were more susceptible to thrushlike lesions, and cyclosporine A was correspondingly less active in this mouse strain. Immunosuppression with cyclosporine A affects host defense mechanisms which are operative against superficial candidiasis but appear superfluous in resistance to the invasive form of this mycosis, an indication for the divergent nature of host defense against the two forms of candidiasis.     

Immunomodulatory effects of anti-CD4 antibody in host resistance against infections and tumors in human CD4 transgenic mice

Anti-CD4 antibodies, which cause CD4(+) T-cell depletion, have been shown to increase susceptibility to infections in mice. Thus, development of anti-CD4 antibodies for clinical use raises potential concerns about suppression of host defense mechanisms against pathogens and tumors. The anti-human CD4 antibody keliximab, which binds only human and chimpanzee CD4, has been evaluated in host defense models using murine CD4 knockout-human CD4 transgenic (HuCD4/Tg) mice. In these mice, depletion of CD4(+) T cells by keliximab was associated with inhibition of anti-Pneumocystis carinii and anti-Candida albicans antibody responses and rendered HuCD4/Tg mice susceptible to P. carinii, a CD4-dependent pathogen, but did not compromise host defense against C. albicans infection. Treatment of HuCD4/Tg mice with corticosteroids impaired host immune responses and decreased survival for both infections. Resistance to experimental B16 melanoma metastases was not affected by treatment with keliximab, in contrast to an increase in tumor colonization caused by anti-T cell Thy1.2 and anti-asialo GM-1 antibodies. These data suggest an immunomodulatory rather than an overt immunosuppressive activity of keliximab. This was further demonstrated by the differential effect of keliximab on type 1 and type 2 cytokine expression in splenocytes stimulated ex vivo. Keliximab caused an initial up-regulation of interleukin-2 (IL-2) and gamma interferon, followed by transient down-regulation of IL-4 and IL-10. Taken together, the effects of keliximab in HuCD4/Tg mice suggest that in addition to depleting circulating CD4(+) T lymphocytes, keliximab has the capability of modulating the function of the remaining cells without causing general immunosuppression. Therefore, keliximab therapy may be beneficial in controlling certain autoimmune diseases.     

Inoculation candidiasis in a murine model of severe combined immunodeficiency syndrome.

To further elucidate the importance of T- and B-lymphocyte-mediated responses in host defense against systemic infection with Candida albicans, we studied this infection in a murine model of severe combined immunodeficiency (SCID). The course of inoculation candidiasis in these mice, which lack functional T and B lymphocytes, was compared with that in immunologically normal BALB/c mice. Mice were inoculated intravenously with 10(5) yeast cells. Quantitative cultures of liver, spleen, and kidneys were performed with necropsy specimens obtained 1, 3, 7, 10, 14, and 21 days after this intravenous inoculation. The differences in the time courses of recovery of organisms from liver and spleen specimens were not significantly different in the SCID mice compared with the BALB/c mice. The recovery of C. albicans from the kidneys was significantly lower in the SCID mice, indicating less persistence of the organism in the kidneys of the SCID mice than in those of the BALB/c mice. These data indicate that defense mechanisms other than T- and B-lymphocyte-mediated mechanisms are primarily responsible for host defense against inoculation candidiasis.     

Gamma interferon as a crucial host defense against Rickettsia conorii in vivo.

Gamma interferon (IFN-gamma) plays an important role as a host defense in rickettsial infection. Swiss Webster mice, which are resistant to Rickettsia conorii (Malish 7 strain) infection, were treated with a monoclonal antibody against mouse IFN-gamma. When the antibody-treated mice were inoculated with 12 50% tissue culture infective doses of R. conorii, the mortality was 47% and the morbidity was 100%. None of the control mice, which received the same dose of R. conorii, died or became ill. The enumeration of rickettsiae in organs by direct immunofluorescence in paraffin sections demonstrated higher quantities of rickettsiae in the spleen had liver of IFN-gamma-depleted mice as compared with those of the infected controls. The kinetic analysis of IFN-gamma levels in sera showed depletion in the treated mice. These results indicate that IFN-gamma plays an important role as a host defense in the early stage of rickettsial infection. Survival of some mice despite continued treatment with antibody to IFN-gamma suggests that other immune mechanisms may also be important.     

Differential role of IL-18 and IL-12 in the host defense against disseminated Candida albicans infection

IFN-gamma plays a crucial role in the defense against infection with Candida albicans. Since IL-18 and IL-12 are strong stimuli of IFN-gamma production, we investigated whether endogenous IL-18 and IL-12 are involved in the host defense during disseminated candidiasis. IL-18 knockout (IL-18-/-) mice, but not IL-12-/- mice, displayed an increased mortality due to C. albicans infection, accompanied by a decreased clearance of the yeasts from the kidneys late during the course of infection. Histopathology of the organs, combined with phagocyte recruitment experiments, showed a decreased influx of monocytes at the sites of Candida infection, mainly in the IL-18-/- mice. Whereas production of the chemokine KC was decreased in both IL-18-/- and IL-12-/- mice, MIP-2 production was deficient only in IL-18-/- animals, which may explain the differences in phagocyte recruitment. In addition, although IFN-gamma production capacity, as a parameter of the Th1-protective immunity, was reduced by 65 to 80% in the IL-12-/- mice, this defect was even more pronounced in the IL-18-/- mice (85 to 95% down-modulation). In conclusion, the anticandidal effects of endogenous IL-18 are mediated late during the infection by assuring a proper IFN-gamma response and promoting the infiltration of the site of infection by monocytes.     

Candida-specific antibodies during experimental vaginal candidiasis in mice

Protective host defense mechanisms against vaginal Candida albicans infections are poorly understood. Although cell-mediated immunity (CMI) is the predominant host defense mechanism against most mucosal Candida infections, the role of CMI against vaginal candidiasis is uncertain, both in humans and in an experimental mouse model. The role of humoral immunity is equally unclear. While clinical observations suggest a minimal role for antibodies against vaginal candidiasis, an experimental rat model has provided evidence for a protective role for Candida-specific immunoglobulin A (IgA) antibodies. Additionally, Candida vaccination-induced IgM and IgG3 antibodies are protective in a mouse model of vaginitis. In the present study, the role of infection-induced humoral immunity in protection against experimental vaginal candidiasis was evaluated through the quantification of Candida-specific IgA, IgG, and IgM antibodies in serum and vaginal lavage fluids of mice with primary and secondary (partially protected) infection. In na?ve mice, total, but not Candida-specific, antibodies were detected in serum and lavage fluids, consistent with lack of yeast colonization in mice. In infected mice, Candida-specific IgA and IgG antibodies were induced in serum with anamnestic responses to secondary infection. In lavage fluid, while Candida-specific antibodies were detectable, concentrations were extremely low with no anamnestic responses in mice with secondary infection. The incorporation of alternative protocols-including infections in a different strain of mice, prolongation of primary infection prior to secondary challenge, use of different enzyme-linked immunosorbent assay capture antigens, and concentration of lavage fluid-did not enhance local Candida-specific antibody production or detection. Additionally, antibodies were not removed from lavage fluids by being bound to Candida during infection. Together, these data suggest that antibodies are not readily present in vaginal secretions of infected mice and thus have a limited natural protective role against infection.     

Retardation of early-onset PMA-induced apoptosis in mouse neutrophils deficient in myeloperoxidase.

Neutrophil apoptosis is a mechanism involved in the resolution of inflammation. To explore the role of hypochlorous acid (HOCl) produced by neutrophils while they are undergoing apoptosis, we compared the rates of apoptosis in neutrophils isolated from normal mice and from myeloperoxidase (MPO)-deficient mice, which are unable to generate HOCl. Apoptosis in MPO-deficient neutrophils stimulated by phorbol myristate acetate (PMA) was significantly slower than in normal neutrophils during 3 h of incubation. Exposure of normal neutrophils to H(2)O(2) together with PMA resulted in a dramatic acceleration of apoptosis, and almost all of the cells revealed apoptotic morphology at 1 h. This acceleration was inhibited by cytochrome c, a superoxide scavenger. Conversely, in MPO-deficient neutrophils activated with PMA and H(2)O(2), little acceleration was observed before 1 h, although it gradually increased thereafter. This retardation was almost completely reversed when MPO or HOCl was exogenously added. These results suggest that coexistence of HOCl and superoxide accelerates the early onset of neutrophil apoptosis.     

The protective immune response against vaginal candidiasis: lessons learned from clinical studies and animal models

Recurrent vulvovaginal candidiasis (RVVC) is a significant problem in women of childbearing ages and is caused by Candida albicans, a commensal organism of the intestinal and reproductive tracts. As a result of this commensalism, most healthy individuals have demonstrable Candida-specific adaptive immunity that is considered protective. In women with RVVC, a deficiency/dysfunction of this protective immunity is postulated to affect susceptibility to infection. Although cell-mediated immunity (CMI) is considered important for protection against mucosal candidal infections, little is understood about specific host defenses that are important at the vaginal mucosa. Studies to date suggest that a compartmentalized local, rather than systemic, immunity is important for defense against vaginitis. This review will summarize the current state of knowledge regarding protective host defense mechanisms against vaginal C. albicans infections both from clinical studies and animal models. From these data, hypotheses are presented for what host defense mechanisms appear important for resistance/susceptibility to vaginal infection.     

THE PROTECTIVE IMMUNE RESPONSE AGAINST VAGINAL CANDIDIASIS: LESSONS LEARNED FROM CLINICAL STUDIES AND ANIMAL MODELS

Recurrent vulvovaginal candidiasis (RVVC) is a significant problem in women of childbearing ages and is caused by Candida albicans, a commensal organism of the intestinal and reproductive tracts. As a result of this commensalism, most healthy individuals have demonstrable Candida -specific adaptive immunity that is considered protective. In women with RVVC, a deficiency/dysfunction of this protective immunity is postulated to affect susceptibility to infection. Although cell-mediated immunity (CMI) is considered important for protection against mucosal candidal infections, little is understood about specific host defenses that are important at the vaginal mucosa. Studies to date suggest that a compartmentalized local, rather than systemic, immunity is important for defense against vaginitis. This review will summarize the current state of knowledge regarding protective host defense mechanisms against vaginal C. albicans infections both from clinical studies and animal models. From these data, hypotheses are presented for what host defense mechanisms appear important for resistance/susceptibility to vaginal infection.     

Candida-specific Th1-type responsiveness in mice with experimental vaginal candidiasis.

The role of systemic cell-mediated immunity (CMI) as a host defense mechanism in the vagina is poorly understood. Using a murine pseudoestrus model of experimental vaginal candidiasis, we previously found that animals given a vaginal inoculum of viable Candida albicans blastoconidia acquired a persistent vaginal infection and developed Candida-specific delayed-type hypersensitivity (DTH) responses. The present study was designed to characterize the peripheral CMI reactivity generated from the vaginal infection in mice and to determine whether pseudoestrus is a prerequisite for the induction of peripheral CMI reactivity. Mice treated or not treated with estrogen and given a vaginal inoculum of C. albicans blastoconidia were examined for 4 weeks for their vaginal Candida burden and peripheral CMI reactivity, including DTH responsiveness and in vitro Th1 (interleukin-2 [IL-2], gamma interferon [IFN-gamma]/Th2 (IL-4, IL-10)-type lymphokine production in response to Candida antigens. Results showed that although mice not treated with estrogen before being given a vaginal inoculum of C. albicans blastoconidia developed only a short-lived vaginal infection and harbored significantly fewer Candida CFU in the vagina compared with those given estrogen and then infected; DTH reactivity was equivalent in both groups. In vitro measurement of CMI reactivity further showed that lymph node cells from both estrogen- and non-estrogen-treated infected mice produced elevated levels of IL-2 and IFN-gamma in response to Candida antigens during the 4 weeks after vaginal inoculation. In contrast, lymph node cells from the same vaginally infected mice showed no IL-10 production and only small elevations of IL-4 during week 4 of infection. These results suggest that mice with experimental vaginal candidiasis develop predominantly Th1-type Candida-specific peripheral CMI reactivity and that similar patterns of Th1-type reactivity occur in mice regardless of the persistence of infection and the estrogen status of the infected mice.     

Human C-reactive protein is protective against fatal Salmonella enterica serovar typhimurium infection in transgenic mice

C-reactive protein (CRP) is an acute-phase protein with a well-known association with infection and other inflammatory conditions. We have shown that expression of human CRP by CRP transgenic (CRPtg) mice is protective against lethal infection by Streptococcus pneumoniae, an effect likely mediated by CRP's ability to bind to this gram-positive pathogen. In the present study we tested whether CRPtg mice are resistant to infection with Salmonella enterica serovar Typhimurium, a gram-negative pathogen that causes the murine equivalent of typhoid fever. CRPtg mice experimentally infected with a virulent Typhimurium strain lived longer and had significantly lower mortality than their non-tg littermates. The greater resistance of CRPtg mice could be attributed to significantly increased early (0 to 4 h) blood clearance of salmonellae and significantly decreased numbers of bacteria in the liver and spleen on day 7 postinfection. In addition, 14 days after infection with an avirulent Salmonella strain, the serum titer of anti-Salmonella immunoglobulin G antibodies was higher in CRPtg than non-tg mice. This study provides unequivocal evidence that CRP plays an important role in vivo in host defense against salmonellae during the early stages of infection. In addition, as the beneficial effect of CRP includes enhancement of the host's humoral immune response, CRP may also contribute indirectly to host defense during later stages of infection.