Expression of intra- and extracellular granzymes in patients with typhoid fever.

BACKGROUND: Typhoid fever, caused by the intracellular pathogen Salmonella (S.) enterica serovar Typhi, remains a major cause of morbidity and mortality worldwide. Granzymes are serine proteases promoting cytotoxic lymphocytes mediated eradication of intracellular pathogens via the induction of cell death and which can also play a role in inflammation. We aimed to characterize the expression of extracellular and intracellular granzymes in patients with typhoid fever and whether the extracellular levels of granzyme correlated with IFN-γ release. METHODS AND PRINCIPAL FINDINGS: We analyzed soluble protein levels of extracellular granzyme A and B in healthy volunteers and patients with confirmed S. Typhi infection on admission and day of discharge, and investigated whether this correlated with interferon (IFN)-γ release, a cytokine significantly expressed in typhoid fever. The intracellular expression of granzyme A, B and K in subsets of lymphocytic cells was determined using flow cytometry. Patients demonstrated a marked increase of extracellular granzyme A and B in acute phase plasma and a correlation of both granzymes with IFN-γ release. In patients, lower plasma levels of granzyme B, but not granzyme A, were found at day of discharge compared to admission, indicating an association of granzyme B with stage of disease. Peripheral blood mononuclear cells of typhoid fever patients had a higher percentage of lymphocytic cells expressing intracellular granzyme A and granzyme B, but not granzyme K, compared to controls. CONCLUSION: The marked increase observed in extra- and intracellular levels of granzyme expression in patients with typhoid fever, and the correlation with stage of disease, suggests a role for granzymes in the host response to this disease.

Clinical and immunogenetic factors associated with pneumonia in patients with systemic lupus erythematosus: a case-control study.

OBJECTIVE: To determine the incidence of pneumonia and associated factors in a single-center systemic lupus erythematosus (SLE) cohort. METHODS: We included all our SLE patients [1997 American College of Rheumatology (ACR) criteria] with ≥ 1 pneumonia event, and 196 age and sex-matched SLE controls with no pneumonia events. Cumulative clinical data, weighted Systemic Lupus International Collaborating Clinics/ACR damage index (wSLICC/ACR-DI), comorbidities, and risk factors for pneumonia were retrospectively collected. The standardized incidence ratio (SIR) of pneumonia was estimated. Polymorphisms at genes coding for mannose binding lectin (MBL), MBL-associated serine protease 2, Fc-gamma receptors, and surfactant proteins A1, A2, and D were determined, and their potential association with pneumonia was analyzed. Patients with and without pneumonia were compared using a multivariate logistic regression model for adjustment of pneumonia-associated factors. RESULTS: Thirty-six of 232 patients with SLE had experienced ≥ 1 pneumonia event. SIR for pneumonia was 5.1 (95% CI 3.5-7.4; p < 0.0001). Excluding patients receiving immunosuppressive therapy at the time of pneumonia (13%), associations were found for Katz Severity Index (KSI) (p = 0.016), wSLICC/ACR-DI (p = 0.044), number of SLE criteria (p = 0.005), hospital admissions (p < 0.001), FCGR2A HH genotype (p = 0.03), previous use of immunosuppressive therapy (p = 0.049), cutaneous ulcers (p < 0.001), and vasculitis (p = 0.008) in bivariate analyses. In the multivariate analysis adjusted to previous immunosuppressive treatment, only KSI and FCGR2A HH genotype remained statistically significant (p = 0.05 and p = 0.03, respectively). CONCLUSION: The incidence of pneumonia in patients with SLE is higher than that in the general population, and particularly high in severe SLE, regardless of immunosuppressive therapy. The HH genetic variant of FCGR2A appears to predispose patients with SLE to pneumonia.

Surfactant protein A genetic variants associate with severe respiratory insufficiency in pandemic influenza A virus infection.

INTRODUCTION: Inherited variability in host immune responses influences susceptibility and outcome of Influenza A virus (IAV) infection, but these factors remain largely unknown. Components of the innate immune response may be crucial in the first days of the infection. The collectins surfactant protein (SP)-A1, -A2, and -D and mannose-binding lectin (MBL) neutralize IAV infectivity, although only SP-A2 can establish an efficient neutralization of poorly glycosylated pandemic IAV strains. METHODS: We studied the role of polymorphic variants at the genes of MBL (MBL2), SP-A1 (SFTPA1), SP-A2 (SFTPA2), and SP-D (SFTPD) in 93 patients with H1N1 pandemic 2009 (H1N1pdm) infection. RESULTS: Multivariate analysis showed that two frequent SFTPA2 missense alleles (rs1965708-C and rs1059046-A) and the SFTPA2 haplotype 1A(0) were associated with a need for mechanical ventilation, acute respiratory failure, and acute respiratory distress syndrome. The SFTPA2 haplotype 1A(1) was a protective variant. Kaplan-Meier analysis and Cox regression also showed that diplotypes not containing the 1A(1) haplotype were associated with a significantly shorter time to ICU admission in hospitalized patients. In addition, rs1965708-C (P = 0.0007), rs1059046-A (P = 0.0007), and haplotype 1A(0) (P = 0.0004) were associated, in a dose-dependent fashion, with lower PaO2/FiO2 ratio, whereas haplotype 1A(1) was associated with a higher PaO2/FiO2 ratio (P = 0.001). CONCLUSIONS: Our data suggest an effect of genetic variants of SFTPA2 on the severity of H1N1pdm infection and could pave the way for a potential treatment with haplotype-specific (1A(1)) SP-A2 for future IAV pandemics.

Survey of emm-like gene sequences from pharyngeal isolates of group C and group G streptococci collected in Spain.

We conducted a nationwide surveillance of the variable 5' emm-like (M-like protein gene) sequences from 214 pharyngeal group C and group G streptococci. Almost 75% of the isolates exhibited emm or emm-like sequences previously described. We identified six new 5' emm-like regions, and almost 23% of the isolates were nontypeable. Five emm-like sequences accounted for more than 50% of the isolates in group C and group G, suggesting horizontal gene transfer between strains of different species.