Seroincidence of Coccidioidomycosis during military desert training exercises.
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Coccidioidomycosis is a common fungal infection acquired in the southwestern United States. This is the first study in over 2 decades to determine the seroincidence of Coccidioides immitis infections among U.S. military members performing training exercises in an area of endemicity. Only 8% of participants were aware of coccidioidomycosis, despite the majority having visited or lived previously in an area of endemicity. One (0.6%) of the 178 participants developed "definite" serologic evidence of infection over a 5-week training period; four (2.3%) additional patients developed "possible" coccidioidomycosis infections. None had complicated disease. The calculated annual incidence ranged from 6 to 32%. This study suggests that the risk of serious coccidioidomycosis is low among military personnel during desert training exercises; however, disease incidence may vary depending on specific activities and geographic factors. Due to the potential morbidity and mortality of this infection, preventative strategies, including vaccine development, are advocated. (+info)
Coccidioidomycosis: host response and vaccine development.
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Coccidioidomycosis is caused by the dimorphic fungi in the genus Coccidioides. These fungi live as mycelia in the soil of desert areas of the American Southwest, and when the infectious spores, the arthroconidia, are inhaled, they convert into the parasitic spherule/endospore phase. Most infections are mild, but these organisms are frank pathogens and can cause severe lethal disease in fully immunocompetent individuals. While there is increased risk of disseminated disease in certain racial groups and immunocompromised persons, the fact that there are hosts who contain the initial infection and exhibit long-term immunity to reinfection supports the hypothesis that a vaccine against these pathogens is feasible. Multiple studies have shown that protective immunity against primary disease is associated with T-helper 1 (Th-1)-associated immune responses. The single best vaccine in animal models, formalin-killed spherules (FKS), was tested in a human trial but was not found to be significantly protective. This result has prompted studies to better define immunodominant Coccidioides antigen with the thought that a subunit vaccine would be protective. These efforts have defined multiple candidates, but the single best individual immunogen is the protein termed antigen 2/proline-rich antigen (Ag2/PRA). Studies in multiple laboratories have shown that Ag2/PRA as both protein and genetic vaccines provides significant protection against mice challenged systemically with Coccidioides. Unfortunately, compared to the FKS vaccine, it is significantly less protective as measured by both assays of reduction in fungal CFU and assays of survival. The capacity of Ag2/PRA to induce only partial protection was emphasized when animals were challenged intranasally. Thus, there is a need to define new candidates to create a multivalent vaccine to increase the effectiveness of Ag2/PRA. Efforts of genomic screening using expression library immunization or bioinformatic approaches to identify new candidates have revealed at least two new protective proteins, expression library immunization antigen 1 (ELI-Ag1) and a beta-1,3-glucanosyltransferase (GEL-1). In addition, previously discovered antigens such as Coccidioides-specific antigen (CSA) should be evaluated in assays of protection. While studies have yet to be completed with combinations of the current candidates, the hypothesis is that with increased numbers of candidates in a multivalent vaccine, there will be increased protection. As the genome sequences of the two Coccidioides strains which are under way are completed and annotated, the effort to find new candidates can increase to provide a complete genomic scan for immunodominant proteins. Thus, much progress has been made in the discovery of subunit vaccine candidates against Coccidioides and there are several candidates showing modest levels of protection, but for complete protection against pulmonary challenge we need to continue the search for additional candidates. (+info)
Coccidioides posadasii infection alters the expression of pulmonary surfactant proteins (SP)-A and SP-D.
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BACKGROUND: Coccidioidomycosis or Valley Fever is caused by Coccidioides in Southwest US and Central America. Primary pulmonary infection is initiated by inhalation of air-borne arthroconidia. Since, lung is the first organ that encounters arthroconidia, different components of the pulmonary innate immune system may be involved in the regulation of host defense. Pulmonary surfactant proteins (SP)-A and SP-D have been recognized to play an important role in binding and phagocytosis of various microorganisms, but their roles in Coccidioides infection are not known. METHODS: In this study, we studied the changes in amounts of pulmonary SP-A, SP-D and phospholipid in murine model of Coccidioides posadasii infection, and binding of SP-A and SP-D to Coccidioidal antigens. Mice were challenged intranasally with a lethal dose of C. posadasii (n = 30 arthroconidia) and bronchoalveolar lavage fluid (BALF) samples were collected on day 10, post infection. In another group of animals, mice were immunized with protective formalin killed spherule (FKS) vaccine prior to infection. The concentrations of BALF SP-A, SP-D, total phospholipid were measured using enzyme linked immunosorbent assay and biochemical assays. RESULTS: We found that in lavage fluid samples of C. posadasii infected mice, the concentrations of total phospholipid, SP-A and SP-D were 17 % (SEM 3.5, p < 0.001), 38 % (SEM 5.8, p < 0.001) and 4 % (SEM 1.3, p < 0.001) of those in lavage fluid samples of non-infected control mice, respectively. However, the concentrations of SP-A and SP-D remained unchanged in BALF samples of C. posadasii protected mice after immunization with FKS vaccine. Also, we found that both SP-A and SP-D bind to Coccidiodal antigens. CONCLUSION: Our results suggest that the C. posadasii infection perturbs the pulmonary SP-A, SP-D, and phospholipids, potentially enabling the disease progression and promoting fungal dissemination. (+info)
Coccidioides posadasii contains a single 1,3-beta-glucan synthase gene that appears to be essential for growth.
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1,3-beta-Glucan synthase is responsible for the synthesis of beta-glucan, an essential cell wall structural component in most fungi. We sought to determine whether Coccidioides posadasii possesses genes homologous to known fungal FKS genes that encode the catalytic subunit of 1,3-beta-glucan synthase. A single gene, designated FKS1, was identified, and examination of its predicted protein product showed a high degree of conservation with Fks proteins from other filamentous fungi. FKS1 is expressed at similar levels in mycelia and early spherulating cultures, and expression decreases as the spherules mature. We used Agrobacterium-mediated transformation to create strains that harbor DeltaFKS1::hygB, a null allele of FKS1, and hypothesize that Fks1p function is essential, due to our inability to purify this allele away from a complementing wild-type FKS1 allele in a heterokaryotic strain. The heterokaryon appears normal with respect to growth rate and arthroconidium production; however, microscopic examination of strains with DeltaFKS1::hygB alleles revealed abnormal swelling of hyphal elements. (+info)
Neuroimaging as a guide to predict outcomes for patients with coccidioidal meningitis.
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Sixty-two patients with coccidioidal meningitis underwent neuroimaging. Magnetic resonance imaging detected neuroimaging abnormalities in 76% of patients, and computed tomography scanning detected neuroimaging abnormalities in 41.6%. The most common abnormal neuroimaging findings were hydrocephalus (51.6%), basilar meningitis (46.8%), and cerebral infarction (38.7%). Significantly elevated mortality rates were associated with hydrocephalus and hydrocephalus coexisting with infarction. Basilar meningitis did not influence outcome. Patients without neuroimaging abnormalities had a mortality rate of 7.7%. (+info)
Innate immunity to the pathogenic fungus Coccidioides posadasii is dependent on Toll-like receptor 2 and Dectin-1.
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Coccidioides posadasii is a pathogenic fungus that causes endemic and epidemic coccidioidomycosis in the deserts of North, Central, and South America. How the innate immune system responds to the organism is not well understood. Here we show that elicited mouse peritoneal macrophages respond to spherules (the tissue form of the fungus) by producing proinflammatory cytokines as measured by quantitative PCR of cellular transcripts and by enzyme-linked immunosorbent assay (ELISA) assays for secreted protein. We examined the contribution of Toll-like receptors (TLR) and MyD88 in macrophage responses to formalin-killed spherules (FKS) by comparing cytokine responses of elicited macrophages from different knockout mice. FKS were added to elicited mouse peritoneal macrophages from wild-type, TLR2-/-, and MyD88-/- cells, and wild-type cells made more tumor necrosis factor alpha, MIP-2, and interleukin 6 than did the mutant macrophages. In contrast, the C3H/HeJ mice, which have a point mutation in TLR4, and TLR4-/- B6 mice exhibited no defect in cytokine production compared to the control mice. We also investigated the role of the macrophage beta-glucan receptor, Dectin-1. RAW 264.7 macrophages overexpressing Dectin-1 produced more cytokines in respond to FKS, live spherules, and purified beta-glucan than did control RAW cells. Blockage of Dectin-1 with antibodies inhibited cytokine production in elicited mouse peritoneal macrophages. Taken together, these results show that cytokine responses in mouse peritoneal macrophages to C. posadasii spherules are dependent on TLR2, MyD88, and Dectin-1. (+info)
Pulmonary coccidioidomycosis that formed a fungus ball with 8-years duration.
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Coccidioidomycosis, caused by inhaling Coccidioides immitis, is a mycosis imported from endemic regions including the southwestern United States. C. immitis is so virulent that even a short-term stay in the endemic area can provide a chance for infection. Here, we report a 33-year-old Japanese man with formation of a fungus ball inside the pulmonary cavity secondary to coccidioidomycosis with a duration of 8 years, which is considered rare. He was infected with C. immitis in the United States in 1996. A nodule remained in the lung, which later cavitated with fungus ball formation. We identified Coccidioides immitis in the cultured specimen from the cavity and serum antibodies against it. We performed a lobectomy in 2003 since anti-fungal treatment was only temporarily effective. He is still free of disease 6 months later. (+info)
Disseminated coccidioidomycosis in an immunocompetent person living in New York City.
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Coccidioidomycosis is a disease caused by Coccidioides immitis, a soil-inhabiting fungus endemic to the desert climate of the southwestern United States and Central and South America. We report a case of disseminated coccidioidomycosis in a previously healthy person living in New York City, who was initially thought to have tuberculosis. The incidence of coccidioidomycosis has been increasing in both endemic and nonendemic areas, but diagnosis is often delayed or missed in nonendemic areas, resulting in extensive and unnecessary medical workup for other diseases or progression to serious disease. Therefore, clinicians should increase their awareness and consideration of this disease in patients with chronic systemic illness. (+info)