Serotype III Streptococcus agalactiae from Bovine Milk and Human Neonatal Infections1

Although largely unrelated, many bovine type III GBS appear to share a common ancestor with an important human clone

Regulation of apoptosis by gram-positive bacteria: Mechanistic diversity and consequences for immunity

Apoptosis, or programmed cell death (PCD), is an important physiological mechanism, through which the human immune system regulates homeostasis and responds to diverse forms of cellular damage. PCD may also be involved in immune counteraction to microbial infection. Over the past decade, the amount of research on bacteria-induced PCD has grown tremendously, and the implications of this mechanism on immunity are being elucidated. Some pathogenic bacteria actively trigger the suicide response in critical lineages of leukocytes that orchestrate both the innate and adaptive immune responses; other bacteria proactively prevent PCD to benefit their own survival and persistence. Currently, the microbial virulence factors, which represent the keys to unlocking the suicide response in host cells, are a primary focus of this field. In this review, we discuss these bacterial "apoptosis regulatory molecules" and the apoptotic events they either trigger or prevent, the host target cells of this regulatory activity, and the possible ramifications for immunity to infection. Gram-positive pathogens including Staphylococcus, Streptococcus, Bacillus, Listeria, and Clostridia species are discussed as important agents of human infection that modulate PCD pathways in eukaryotic cells

Nitric oxide is a key determinant of group B streptococcus-induced murine macrophage apoptosis

Group B streptococcus (GBS; Streptococcus agalactiae) induces apoptosis of macrophages, and this may be an important mechanism GBS uses to suppress immune responses. The mechanisms whereby GBS induces apoptosis have not been identified. We studied GBS infection in murine macrophage - like J774A.1 cells and analyzed gene expression before apoptosis. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and inducible nitric oxide synthase ( iNOS) gene expression coincided with apoptosis. Inhibition of iNOS gene expression by use of N-G-monomethyl-L-arginine ( NMMA) inhibited apoptosis, whereas inhibition of TNF-alpha and IL-1 biological activity did not. Macrophages from congenic iNOS-deficient mice were less susceptible to apoptosis than were macrophages from C57BL/6 mice. The NO donor S-nitroso-N-acetylpenicillamine ( SNAP) induced apoptosis without infection, confirming its proapoptotic effect. NMMA did not impair the microbicidal activity of macrophages, however, and SNAP was not bactericidal against GBS in vitro. In human monocyte - derived macrophages (HMDMs), NO production was minimal, even after costimulation with IFN-gamma and lipopolysaccharide. Dose-dependent apoptosis of HMDMs occurred without a significant NO response. Thus, NO is an important mediator of GBS-induced murine macrophage apoptosis but does not contribute to antimicrobial activity or cytotoxicity in HMDMs. HMDMs and murine macrophages are killed by GBS by alternative, NO-independent mechanisms. Future studies of host-cell machinery commandeered by GBS to bring about apoptosis will be important for understanding the role played by apoptosis in defense against this important human pathogen

Nontypeable Haemophilus influenzae Adheres to Intercellular Adhesion Molecule 1 (ICAM-1) on Respiratory Epithelial Cells and Upregulates ICAM-1 Expression

Nontypeable Haemophilus influenzae (NTHI) is an important respiratory pathogen. NTHI initiates infection by adhering to the airway epithelium. Here, we report that NTHI interacts with intracellular adhesion molecule 1 (ICAM-1) expressed by respiratory epithelial cells. A fourfold-higher number of NTHI bacteria adhered to Chinese hamster ovary (CHO) cells transfected with human ICAM-1 (CHO-ICAM-1) than to control CHO cells (P ≤ 0.005). Blocking cell surface ICAM-1 with specific antibody reduced the adhesion of NTHI to A549 respiratory epithelial cells by 37% (P = 0.001) and to CHO-ICAM-1 cells by 69% (P = 0.005). Preincubating the bacteria with recombinant ICAM-1 reduced adhesion by 69% (P = 0.003). The adherence to CHO-ICAM-1 cells of NTHI strains deficient in the adhesins P5, P2, HMW1/2, and Hap or expressing a truncated lipooligosaccharide was compared to that of parental strains. Only strain 1128f(−), which lacks the outer membrane protein (OMP) P5-homologous adhesin (P5 fimbriae), adhered less well than its parental strain. The numbers of NTHI cells adhering to CHO-ICAM-1 cells were reduced by 67% (P = 0.009) following preincubation with anti-P5 antisera. Furthermore, recombinant ICAM bound to an OMP preparation from strain 1128f(+), which expresses P5, but not to that from its P5-deficient mutant, confirming a specific interaction between ICAM-1 and P5 fimbriae. Incubation of respiratory epithelial cells with NTHI increased ICAM-1 expression fourfold (P = 0.001). Adhesion of NTHI to the respiratory epithelium, therefore, upregulates the expression of its own receptor. Blocking interactions between NTHI P5 fimbriae and ICAM-1 may reduce respiratory colonization by NTHI and limit the frequency and severity of NTHI infection

Subtractive Hybridization Identifies a Novel Predicted Protein Mediating Epithelial Cell Invasion by Virulent Serotype III Group B Streptococcus agalactiae

Group B Streptococcus agalactiae bacteria (group B streptococci [GBS]) are the most common cause of serious bacterial infection in newborn infants. The majority of serotype III-related cases of neonatal disease are caused by a genetically related subgroup of bacteria, restriction fragment digest pattern (RDP) type III-3, suggesting that these strains possess unique genes contributing to virulence. We used genomic subtractive hybridization to identify regions of genomic DNA unique to virulent RDP type III-3 GBS strains. Within one of these III-3-specific regions is a 1,506-bp open reading frame, spb1 (surface protein of group B streptococcus 1). A mutant type III GBS strain lacking Spb1 was constructed in virulent RDP type III-3 strain 874391, and the interactions of the wild-type and spb1 isogenic mutant with a variety of epithelial cells important to GBS colonization and infection were compared. While adherence of the spb1 isogenic mutant to A549 respiratory, C2Bbe1 colonic, and HeLa cervical epithelial cells was slightly lower than that of the 874391 strain, invasion of the Spb1(−) mutant was significantly reduced with these cell lines compared to what was seen with 874391. The defect in epithelial invasion was corrected by supplying spb1 in trans. These observations suggest that Spb1 contributes to the pathogenesis of neonatal GBS infection by mediating internalization of virulent serotype III GBS and confirm that understanding of the population structure of bacteria may lead to insights into the pathogenesis of human infections

Mucormycosis in children with cancer and hematopoietic cell transplant-A single center cohort study.

Although mucormycosis is an important cause of morbidity and mortality in children with cancer, our understanding of the typical characteristics of these infections is incomplete. We reviewed all cases of mucormycosis diagnosed at a single pediatric cancer center over 5 decades to identify the clinical features of mucormycosis in pediatric oncology patients and to identify risk factors for mortality. There were 44 cases of mucormycosis diagnosed between 1970-2019. Most patients (89%) had hematological malignancies and a history of prolonged and severe neutropenia (91%). In this series, hyperglycemia and exposure to corticosteroids were common. Pulmonary (36%) and disseminated infections (32%) were most common; rhino-orbital-cerebral infections were relatively infrequent (11%). Rhizopus spp. was the most common etiological agent (40%) followed by Mucor spp. (31%), and Cunninghamella spp. (19%). Overall mortality was 44% and 51% and attributable mortality was 39% and 41% at the end of antifungal therapy and end of follow up, respectively. Attributable mortality fell to 18% in 2010-2019, from 58-60% in previous decades; adjunctive surgery was associated with decreased mortality. Mortality remains unacceptably high despite aggressive antifungal therapy and adjunctive surgery, suggesting novel therapeutic strategies are needed