Background Campylobacter jejuni is the leading antecedent infection to the autoimmune neuropathy Guillain-Barré syndrome (GBS), which is accompanied by an autoimmune anti-ganglioside antibody attack on peripheral nerves. Previously, we showed that contrasting immune responses mediate C. jejuni induced colitis and autoimmunity in interleukin-10 (IL-10)-deficient mice, dependent upon the infecting strain. Strains from colitis patients elicited T helper 1 (TH1)-dependent inflammatory responses while strains from GBS patients elicited TH2-dependent autoantibody production. Both syndromes were exacerbated by antibiotic depletion of the microbiota, but other factors controlling susceptibility to GBS are unknown.MethodsUsing 16S rRNA gene high-throughput sequencing, we examined whether structure of the gut microbial community alters host (1) gastrointestinal inflammation or (2) anti-ganglioside antibody responses after infection with C. jejuni strains from colitis or GBS patients. We compared these responses in C57BL/6 mice with either (1) stable human gut microbiota (Humicrobiota) transplants or (2) conventional mouse microbiota (Convmicrobiota).ResultsInoculating germ-free C57BL/6 wild-type (WT) mice with a mixed human fecal slurry provided a murine model that stably passed its microbiota over >20 generations. Mice were housed in specific pathogen-free (SPF) facilities, while extra precautions of having caretakers wear sterile garb along with limited access ensured that no mouse pathogens were acquired. Humicrobiota conferred many changes upon the WT model in contrast to previous results, which showed only colonization with no disease after C. jejuni challenge. When compared to Convmicrobiota mice for susceptibility to C. jejuni enteric or GBS patient strains, infected Humicrobiota mice had (1) 10-100 fold increases in C. jejuni colonization of both strains, (2) pathologic change in draining lymph nodes but only mild changes in colon or cecal lamina propria, (3) significantly lower Th1/Th17-dependent anti-C. jejuni responses, (4) significantly higher IL-4 responses at 5 but not 7 weeks post infection (PI), (5) significantly higher Th2-dependent anti-C. jejuni responses, and (6) significantly elevated anti-ganglioside autoantibodies after C. jejuni infection. These responses in Humicrobiota mice were correlated with a dominant Bacteroidetes and Firmicutes microbiota.ConclusionsThese data demonstrate that Humicrobiota altered host-pathogen interactions in infected mice, increasing colonization and Th-2 and autoimmune responses in a C. jejuni strain-dependent manner. Thus, microbiota composition is another factor controlling susceptibility to GBS.Electronic supplementary materialThe online version of this article (doi:10.1186/s40168-017-0284-4) contains supplementary material, which is available to authorized users.
Respiratory syncytial virus (RSV) has been reported to use CX3CR1 in vitro as a receptor on cultured primary human airway epithelial cultures. To evaluate CX3CR1 as the receptor for RSV in vivo , we used the cotton rat animal model because of its high permissiveness for RSV infection. Sequencing the cotton rat CX3CR1 gene revealed 91% amino acid similarity to human CX3CR1. Previous work found that RSV binds to CX3CR1 via its attachment glycoprotein (G protein) to infect primary human airway cultures. To determine whether CX3CR1-G protein interaction is necessary for RSV infection, recombinant RSVs containing mutations in the CX3CR1 binding site of the G protein were tested in cotton rats. In contrast to wildtype virus, viral mutants did not grow in the lungs of cotton rats. When RSV was incubated with an antibody blocking the CX3CR1 binding site of G protein and subsequently inoculated intranasally into cotton rats, no virus was found in the lungs four days post-infection. In contrast, growth of RSV was not affected after pre-incubation with heparan sulfate (the receptor for RSV on immortalized cell lines). A reduction in CX3CR1 expression in the cotton rat lung through the use of peptide-conjugated morpholino oligomers led to a 10-fold reduction in RSV titers at day four post-infection. In summary, these results indicate that CX3CR1 functions as a receptor for RSV in cotton rats, and in combination with data from human airway epithelial cell cultures, strongly suggest that CX3CR1 is a primary receptor for naturally acquired RSV infection. Importance The knowledge about a virus receptor is useful to better understand the uptake of a virus into a cell and potentially develop antivirals either directed against the receptor molecule on the cell or the receptor-binding protein of the virus. Amongst a number of potential receptor proteins, human CX3CR1 has been demonstrated to act as receptor for respiratory syncytial virus (RSV) on human epithelial cells in tissue culture. Here we report that the cotton rat CX3CR1 which is similar to the human molecule acts as receptor in vivo. This study strengthens the argument that CX3CR1 is a receptor molecule for RSV.
Case summaryA 9-year-old spayed female domestic shorthair cat with clinical signs suggestive of chronic recurrent otitis media and recent seizures was presented with multifocal nervous system disease, including bilateral central and/or peripheral vestibular, cerebellar and forebrain deficits. Prior to presentation, there was inadequate improvement after 6 weeks of treatment for bilateral middle ear effusion from which a highly susceptible Staphylococcus species was cultured. This was followed by the development of seizures. Results of a complete blood count and serum chemistry were unremarkable, and a previous feline leukemia virus/feline immunodeficiency virus ELISA was negative. The cat was hospitalized overnight and had multiple seizures. The following morning the cat’s mentation worsened, and the cat lost ventilatory drive after induction for anesthesia in preparation for MRI. A brain herniation event was suspected, and the cat was euthanized prior to further diagnostics. On post-mortem examination both tympanic bullae were filled with a soft, tan-colored material. Histologically, this material was composed of neoplastic lymphocytes. In addition, neoplastic lymphocytes were found in the leptomeninges, brain parenchyma, submandibular lymph nodes and pancreas. The neoplastic lymphocytes were negative for both B- and T-lymphocyte immunohistochemical markers and PCR for antigen receptor rearrangements failed to amplify target DNA, indicating non-B, non-T-cell lymphoma.Relevance and novel informationTo our knowledge, this is the first report of lymphoma with confirmed bilateral tympanic bulla involvement in the human and veterinary literature. Neoplasia should be considered in cases of middle-ear effusion that do not improve adequately with appropriate antimicrobial therapy.
Two unrelated bovine beef calves, aged 2 mo and 3 mo, were presented to The Ohio State University Veterinary Medical Center because of scrotal swelling and abdominal distension. On postmortem examination, there was abundant peritoneal fluid and numerous small friable masses covering all peritoneal surfaces and extending into the scrotum via the tunica vaginalis, with no identifiable primary neoplasm. Based on light microscopy, differential diagnoses included malignant mesothelioma and anaplastic carcinoma. Immunohistochemically, the neoplasms labeled positive for cytokeratin, and negative for vimentin and calretinin. Neoplastic cells contained periodic acid-Schiff-positive, diastase-resistant cytoplasmic granules, and lacked Alcian blue-positive, hyaluronidase-negative cytoplasmic vacuoles. Ultrastructurally, the cells had features of carcinoma, including secretory granules, and lacked typical features of mesothelioma, such as long slender microvilli. Our final diagnosis was carcinoma in both calves, despite the equivocal gross and light microscopic findings. We propose that a presumptive diagnosis of peritoneal mesothelioma in bovine calves should be avoided without corroboration by a combination of histology, histochemistry, immunohistochemistry, and, if possible, electron microscopy.
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