Enteric helminths promote Salmonella co-infection by altering the intestinal metabolome

Intestinal helminth infections occur pre dominantly in regions where exposure to enteric bacterial pathogens is also common. Helminth infections inhibit host immunity against microbial pathogens, which has largely been attributed to the induction of regulatory or type 2 (Th2) immune responses. Here we demonstrate an additional three-way interaction in which helminth infection alters the metabolic environment of the host intestine to enhance bacterial pathogenicity. We show that an ongoing helminth infection increased colonization by Salmonella independently of T regulatory or Th2 cells. Instead, helminth infection altered the metabolic profile of the intestine, which directly enhanced bacterial expression of Salmonella pathogenicity island 1 (SPI-1) genes and increased intracellular invasion. These data reveal a novel mechanism by which a helminth-modified metabolome promotes susceptibility to bacterial co-infection

Genital HSV-2 Infection Induces Short-Term NK Cell Memory

NK cells are known as innate immune cells that lack immunological memory. Recently, it has been shown that NK cells remember encounters with chemical haptens that induce contact hypersensitivity and cytomegalovirus infection. Here, we show the existence of NK cell memory following HSV-2 infection. Stimulation with HSV-2 Ags led to higher IFNγ production in NK cells that were exposed 30 days previously to HSV-2, compared to NK cells from naïve mice. More importantly, this increased production of IFNγ in NK cells was independent of B- and T- lymphocytes and specific for the HSV-2 Ags. We also showed that previously exposed NK cells in a B- and T-lymphocyte free environment mediate protection against HSV-2 infection and they are necessary for the protection of mice against HSV-2 infection. Collectively, NK cells remember prior HSV-2 encounters independent of B- and T- lymphocytes leading to protection against HSV-2 mediated morbidity and mortality upon re-exposure

The Intestinal Microbiota Plays a Role in Salmonella-Induced Colitis Independent of Pathogen Colonization

The intestinal microbiota is composed of hundreds of species of bacteria, fungi and protozoa and is critical for numerous biological processes, such as nutrient acquisition, vitamin production, and colonization resistance against bacterial pathogens. We studied the role of the intestinal microbiota on host resistance to Salmonella enterica serovar Typhimurium-induced colitis. Using multiple antibiotic treatments in 129S1/SvImJ mice, we showed that disruption of the intestinal microbiota alters host susceptibility to infection. Although all antibiotic treatments caused similar increases in pathogen colonization, the development of enterocolitis was seen only when streptomycin or vancomycin was used; no significant pathology was observed with the use of metronidazole. Interestingly, metronidazole-treated and infected C57BL/6 mice developed severe pathology. We hypothesized that the intestinal microbiota confers resistance to infectious colitis without affecting the ability of S. Typhimurium to colonize the intestine. Indeed, different antibiotic treatments caused distinct shifts in the intestinal microbiota prior to infection. Through fluorescence in situ hybridization, terminal restriction fragment length polymorphism, and real-time PCR, we showed that there is a strong correlation between the intestinal microbiota composition before infection and susceptibility to Salmonella-induced colitis. Members of the Bacteroidetes phylum were present at significantly higher levels in mice resistant to colitis. Further analysis revealed that Porphyromonadaceae levels were also increased in these mice. Conversely, there was a positive correlation between the abundance of Lactobacillus sp. and predisposition to colitis. Our data suggests that different members of the microbiota might be associated with S. Typhimurium colonization and colitis. Dissecting the mechanisms involved in resistance to infection and inflammation will be critical for the development of therapeutic and preventative measures against enteric pathogens

Overexpression of Interleukin-15 Compromises CD4-Dependent Adaptive Immune Responses against Herpes Simplex Virus 2▿ †

Interleukin-15 (IL-15) is necessary for the development and function of NK/NKT cells and the maintenance of naive and memory CD8+ T cells. In the absence of IL-15, protective innate immunity is not available; however, a functional adaptive immune response against vaginal herpes simplex virus 2 (HSV-2) is generated. Mice overexpressing IL-15 (IL-15tg mice) have higher numbers of NK cells, greater NK-derived gamma interferon, and more CD8+ T cells. Here we examined the consequences of IL-15 overexpression for innate and adaptive immunity against genital HSV-2. Surprisingly, IL-15tg mice immunized against HSV-2 were not protected against genital HSV-2 challenge compared to control immunized mice. IL-15tg mice had a higher frequency of NK cells in the genital mucosa than control mice. However, immunized IL-15tg mice had significantly lower numbers of HSV-2-specific CD4+ T cells than B6 mice. We then confirmed that CD4+ T cells, but not CD8+ T cells, are essential for protection against intravaginal HSV-2 challenge. Since we observed less protection in immunized IL-15tg mice, we then examined if the adaptive immune responses generated in an environment with overexpression of IL-15 could provide protection against HSV-2 in an environment with normal levels of IL-15 expression. We adoptively transferred immunized cells from IL-15tg and B6 mice into naive RAG-1−/− mice and found that the cells from immunized IL-15tg mice were able to provide protection in this IL-15-normal environment. Our data suggest that overexpression of IL-15 results in a reduced CD4+ T cell-mediated adaptive immune response against genital HSV-2

NK and NKT Cell-Independent Contribution of Interleukin-15 to Innate Protection against Mucosal Viral Infection

Interleukin-15 (IL-15) is essential for the development, maturation, and function of NK and NKT cells, which are critical components of the innate immune defense against viral infections. We recently showed that mice lacking IL-15 and/or NK/NKT cells are significantly more susceptible to intravaginal (IVAG) herpes simplex virus type 2 (HSV-2) infection than control mice. For this study, we examined whether IL-15 has any direct antiviral activity, independent of NK/NKT cells, in innate protection against HSV-2 infection. A sensitive enzyme-linked immunosorbent assay for murine IL-15 was developed and used to show that IVAG HSV-2 infection induces IL-15 in vaginal washes. Using immunohistochemistry, we detected IL-15-positive cells in the submucosa and vaginal epithelium following IVAG HSV-2 infection. Local, but not systemic, delivery of murine recombinant IL-15 (mrIL-15) to the genital mucosae of IL-15(−/−) and RAG-2(−/−) γ(c)(−/−) mice, which both lack NK and NKT cells, resulted in significant reductions in HSV-2 titers in genital washes and 60% survival following IVAG HSV-2 challenge. Furthermore, we showed that IL-15 is important for CpG oligodeoxynucleotide (ODN)-induced innate protection against genital HSV-2 infection. While 100% of CpG ODN-treated RAG2(−/−) γ(c)(−/−) mice, which are capable of producing IL-15 but lack NK/NKT cells, survived an IVAG HSV-2 challenge, only 60% of CpG ODN-treated IL-15(−/−) mice survived, and all of these mice had similar vaginal viral titers to those in control mice by day 3 postchallenge. Lastly, a treatment of RAW264.7 cells with mrIL-15 induced the production of tumor necrosis factor alpha and beta interferon (IFN-β), but not IFN-α, and significantly protected them against HSV-2 infection in vitro. The results of these studies indicate that IL-15 can act independently of NK/NKT cells in mediating the innate defense against viral infection

“ICE” – A rare cause for coagulopathy in a case of massive post-partum hemorrhage

A case of massive post-partum hemorrhage in East-Malaysia, associated with 3-4 methylene-dioxy-methamphetamine (MDMA) abuse otherwise known as Ecstasy or locally as “ICE”, injected by the patient as a means to suppress labor pains prior to hospital presentation. We report a rare case of substance abuse that lead to life threatening hemorrhage in a maternal patient of productive age group. Presenting to the labor suite in second stage of labor in breech presentation, exhibiting active neuropsychiatric symptoms of intoxication like euphoria, drowsiness, mydriasis but able to obey commands. A rapid response by the Obstetric on-call team proceeded with an assisted-breech delivery. Post-delivery, a baby girl with poor Apgar score was born and intubated. The mother was then posted for an Examination Under Anesthesia as she was noted to have slow blood oozing per-vaginally using a single shot spinal as she exhibited features of difficult intubation and high risk of aspiration. During the procedure, she tipped into massive PPH complicated with DIVC, and was rushed into the intensive care unit for stabilization and back into the operation theatre, needing a total abdominal hysterectomy (TAH) as definitive bleeding control. She required large scale resuscitative efforts peri-operatively including continuous veno-venous hemofiltration (CVVH) as well as regional intensive care consultation. We describe, chronologically the anesthetic challenges faced in managing a patient in acute substance intoxication at presentation to our district hospital during twilight hours. We then explain the pharmacodynamics of MDMA in provoking coagulopathy. No reports of similar cases in the South-East Asia region