ABSTRACT
Antibodies to Streptococcus gallolyticus subspecies gallolyticus (SGG) have been associated with colorectal cancer (CRC). Because SGG may correlate with impaired gut epithelia, we assessed the association of antibodies to bacterial flagellin C (FliC), a measure potentially related to this impairment, with CRC and the CRC-specific interaction with antibodies to SGG proteins. Antibodies to FliC and SGG pilus proteins Gallo2178 and Gallo2179 were measured in two independent studies, a combined study from Nijmegen and Detroit (93 CRC cases, 74 controls) and a replication data set including 576 cases and 576 controls from the Spanish multicenter multicase-control study (MCC-Spain). Logistic regression was applied to assess whether antibodies to FliC were associated with CRC and modified the association of antibodies to SGG proteins with CRC. Antibodies to FliC were associated with those to SGG Gallo2178 among CRC cases, resulting in an interaction in the association of antibodies to Gallo2178 with CRC (p = 0.007). This association was only present among individuals with high antibody responses to FliC (OR: 2.42, 95% CI: 1.45-4.06). In conclusion, our findings suggest that colorectal tumorigenesis could be accompanied by an impaired integrity of the epithelium that could result in associated increased antibody responses to bacterial proteins.
Subject(s)
Antibodies, Bacterial/immunology , Colorectal Neoplasms/complications , Fimbriae Proteins/immunology , Fimbriae, Bacterial/immunology , Flagellin/immunology , Streptococcal Infections/complications , Streptococcus gallolyticus/immunology , Adult , Aged , Aged, 80 and over , Case-Control Studies , Colorectal Neoplasms/microbiology , Female , Humans , Logistic Models , Male , Middle Aged , Spain , Streptococcal Infections/microbiologyABSTRACT
Gram-positive bacteria deploy the type VII secretion system (T7SS) to facilitate interactions between eukaryotic and prokaryotic cells. In recent work, we identified the TelC protein from Streptococcus intermedius as a T7SS-exported lipid II phosphatase that mediates interbacterial competition. TelC exerts toxicity in the inner wall zone of Gram-positive bacteria; however, intercellular intoxication of sister cells does not occur because they express the TipC immunity protein. In the present study, we sought to characterize the molecular basis of self-protection by TipC. Using sub-cellular localization and protease protection assays, we show that TipC is a membrane protein with an N-terminal transmembrane segment and a C-terminal TelC-inhibitory domain that protrudes into the inner wall zone. The 1.9-Å X-ray crystal structure of a non-protective TipC paralogue reveals that the soluble domain of TipC proteins adopts a crescent-shaped fold that is composed of three α-helices and a seven-stranded ß-sheet. Subsequent homology-guided mutagenesis demonstrates that a concave surface formed by the predicted ß-sheet of TipC is required for both its interaction with TelC and its TelC-inhibitory activity. S. intermedius cells lacking the tipC gene are susceptible to growth inhibition by TelC delivered between cells; however, we find that the growth of this strain is unaffected by endogenous or overexpressed TelC, although the toxin accumulates in culture supernatants. Together, these data indicate that the TelC-inhibitory activity of TipC is only required for intercellularly transferred TelC and that the T7SS apparatus transports TelC across the cell envelope in a single step, bypassing the cellular compartment in which it exerts toxicity en route.
Subject(s)
Bacterial Toxins/metabolism , Streptococcus intermedius/growth & development , Type VII Secretion Systems/chemistry , Type VII Secretion Systems/metabolism , Cell Membrane/metabolism , Crystallography, X-Ray , Mutation , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Streptococcus gallolyticus/genetics , Streptococcus gallolyticus/growth & development , Streptococcus gallolyticus/immunology , Streptococcus intermedius/genetics , Streptococcus intermedius/immunology , Type VII Secretion Systems/geneticsABSTRACT
La infección por HIV suele ser un campo propicio para la aparición de complicaciones de causas inusuales, entre ellas, las infecciones por gérmenes extremadamente infrecuentes. Las distintas subespecies de Streptococcus bovis suelen presentarse como bacteriemias o endocar-ditis asociadas, con mucha frecuencia, a tumores benignos o malignos de las regiones colorrectal, gástrica, pancreática o hepatobiliar.Se presenta un caso raro de meningitis por Streptoccocus gallolyticusen un paciente adulto infectado por HIV, sin evidencia alguna de las asociaciones o localizaciones mencionadas y con características clíni-cas y licuorales que pueden inducir a pensar en diagnósticos distintos y, por ende, a tratamientos no apropiados.Un sistema inmunológico deteriorado suele ser el escenario determi-nante para la emergencia de estas raras complicaciones
HIV infectionis, usually, a favorable field for the development of complications from unusual causes including infections with extremely raregerms. The different subspecies of Streptococcus bovis often present as bacteriemias or endocarditis, most frequently associated with benign or malignant tumors of the colorectal, gastric, pancreatic or hepatobiliary regions.A rare case of meningitis due to Streptoccocus gallolyticus in an adult patient infected by HIV is presented without any evidence of associations or mentioned locations and with clinical and the cerebrospinal fluid features that induce to other diagnoses and subsequent inappropriate treatment.A deteriorated immune system is the determining factor for the emergence of these rare complications