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15 22 January 2020 Joint Pathology Center Veterinary Pathology Services WEDNESDAY SLIDE CONFERENCE 2019-2020 C o n f e r e n c e 15 22 January 2020 Dr. Cory Brayton, DVM, PhD, DACVP, DACLAM, Director, Phenotypic Core Associate Professor of Molecular and Comparative and Pathobiology Johns Hopkins School of Medicine Baltimore MD CASE I: 16N131-1 (JPC 4128009). Microscopic Description: In sections of brain, there was a severe inflammatory Signalment: 3.5mo old, female, NOD.Cg- infiltrate composed exclusively of mature scid tm1Wjl Prkdc Il2rg /SzJ (NOD-SCID- and degenerate neutrophils within the third gamma/NSG) mouse (Mus musculus) and lateral ventricles, extending into the History: This mouse was xenografted in the subjacent neuropil of the hippocampus and mammary fat pad at 6 weeks of age with cerebrum with associated fragmentation and tumor cells from a breast cancer patient. The rarefaction of the neuropil. Several colonies mouse presented moribund, hunched and of short rod-shaped bacteria with peripheral scruffy two months later, and was clearing were observed within areas of subsequently euthanized. necrosis. The meninges were expanded with a mild inflammatory infiltrate composed Gross Pathology: The xenograft tumor was predominantly of neutrophils. In sections of not observed at gross necropsy. The mouse lung, multiple arteries contained variably was in poor body condition, with marked sized accumulations of fibrin, neutrophils, depletion of external and internal adipose and fewer macrophages, some containing stores. The lungs were mottled dark red, and similar rod-shaped bacteria. The the spleen was dark red to black and smaller perivascular interstitium and alveolar walls than normal. The small intestine contained were multifocally thickened with few small amounts of mucous, and few fecal neutrophils and macrophages, some of pellets were present in the descending colon. which contained intracytoplasmic bacteria. In sections of liver, there were few small Laboratory results: N/A. inflammatory foci composed of degenerate neutrophils associated with hepatocellular 1 3. Liver: Hepatitis, suppurative and embolic, multifocal, minimal, with rod-shaped bacterial colonies. 4. Bone marrow: Myeloid hyperplasia, diffuse, marked. Contributor’s Comment: Klebsiella spp. are gram-negative rod-shaped bacteria that are typically commensals in mice, and are not a significant cause of naturally occurring disease. K. oxytoca is ubiquitous in the environment, and can be isolated from the gastrointestinal tract, nasopharynx, lung, Brain, NOD SCID mouse: Multiple sections of the brain are submitted with cerebellum and brainstem skin, and mucous membranes of healthy (top left), diencephalon (middle) and telencephalon animals and humans.2,7,14 However, these (inverted at bottom right). The lateral ventricles organisms may become opportunistic (black arrows), third ventricle (blue arrow) and fourth ventricle (green arrow) are distended and pathogens in certain situations, and in both contain a cellular exudate. (HE, 5X). humans and animals infections with K. pneumoniae and oxytoca are most necrosis and rod-shaped bacteria, and there commonly associated with clinical disease. were increased numbers of inflammatory Klebsiella oxytoca can cause suppurative cell infiltrates within portal areas, composed lesions in various organ systems in mice, primarily of lymphocytes, macrophages, and particularly the reproductive tract, where it fewer neutrophils. Occasionally rod-shaped has been associated with suppurative bacteria were observed in Kupffer cells. In endometritis, salpingitis, and perioophortitis sections of bone marrow, there was diffuse often progressing to peritonitis and abscess and marked myeloid hyperplasia. Hucker- formation. Other reported opportunistic Twort gram stain on sections of brain infections in rats and mice include perianal revealed gram negative rod-shaped bacteria. dermatitis, otitis media, cystitis, pyelonephritis, keratoconjunctivitis, Contributor’s Morphologic Diagnosis: 1. Brain: Meningoencephalitis, suppurative, Harderian gland adenitis, oral infection, locally extensive, severe, with rod-shaped subcutaneous, abdominal and hepatic abscesses, pneumonia, meningitis, bacterial colonies. endotoxemia and septicemia. 1,3,8,14 In 2. Lung: Pneumonia, suppurative and humans, Klebsiella oxytoca and pneumoniae embolic, multifocal, moderate, with rod- are considered important causes of shaped bacterial colonies. nosocomial infections in hospitalized patients, and has been implicated in community acquired pneumonia, adult and 2 Klebsiella spp. infection. Suppurative otitis media, urogenital tract infections, and pneumonia have been reported in substrains of C3H/HeJ mice and NMRI- Foxn1nu mice, and LWE.1AR1 rats, and chronic renal inflammatory lesions and ascending urinary tract infections in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. 1,2,4,7,14 C3H/HeJ substrains are hyporesponsive to lipopolysaccharide (LPS) produced by gram-negative bacteria, due to a single Brain, NOD SCID mouse: Neutrophils occupy the amino acid substitution in the toll-like lateral ventricle and infiltrate the adjacent nu parenchyma, resulting in cavitation and thrombosis receptor 4 (TLR4) protein, NMRI- Foxn1 of parenchymal capillaries (arrows). (HE, 200X). (nude) mice lack a thymus and are therefore (Photo courtesy of: In Vivo Animal Core, Unit for T-cell deficient, and LEW.1AR-iddm rats Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 are at risk for infection secondary to http://animalcare.umich.edu/business-services/vivo- development of diabetes mellitus. Finally, animal-core) NSG mice have multiple mutations neonatal sepsis and bacteremia, septic including the Prkdc severe combined arthritis, soft tissue abscesses, and urinary immune deficiency (scid) mutation, IL2 tract infections, and chronic nasal gamma deficiency, mutation of the C5 infections.1,2,10 K. oxytoca is also suspected complement gene, and a novel MHC to be the etiologic agent responsible for haplotype which leads to lack of normal T antibiotic-associated hemorrhagic colitis (AAHC) in humans, which occurs following antibiotic therapy and is characterized by bloody diarrhea, abdominal cramping and segmental hemorrhagic typhlocolitis 1,2,14. Antibiotic therapy has been shown to promote abnormal colonization by Klebsiella spp. in humans1 and rodents,5 and an animal model of AAHC has been developed using oral administration of antibiotics in rats followed by oral infection Brain, NOD SCID mouse: Neutrophils occupy the 6 with K. oxytoca. lateral ventricle and infiltrate the adjacent parenchyma, resulting in cavitation and thrombosis Immune status of the host plays an integral of parenchymal capillaries (arrows). (HE, 200X). role in the pathogenesis of disease by (Photo courtesy of: In Vivo Animal Core, Unit for Laboratory Animal Medicine, University of Michigan Klebsiella spp. Certain strains and Medical School, Ann Arbor, MI 48109 genetically modified mouse lines are more http://animalcare.umich.edu/business-services/vivo- prone to developing lesions associated with animal-core) 3 and B lymphocytes and NK cells, and staining, the observed peripheral clearing deficient cytokine and complement signaling around the gram-negative, rod-shaped and function.4 Increasing age may also play bacterial organisms is characteristic of a contributory role in pathogenesis of Klebsiella spp. The affected animal in this Klebsiella infection, as suppurative case was a NSG mouse, which as previously reproductive lesions due to K. oxytoca discussed is a severely immunodeficient infection have been reported in National mouse model prone to opportunistic Toxicology Program (NTP) chronic infection. These mice are commonly used to chemical carcinogenesis bioassays.3 model development, progression, and metastasis of human tumor cells in vivo, Klebsiella exerts its pathogenic effects by through xenotransplantation experiments. taking advantage of an immunosuppressed or immunocompromised host, and through the use of several virulence factors. The presence of a distinct polysaccharide capsule observed as a peripheral clearing on routine light microscopy is correlated with virulence of the organism, enabling it to resist phagocytosis and bactericidal components of serum.1,7,10 In addition, several in vitro studies in humans and in mice have shown that K. oxytoca produces a cytotoxin, tilivalline, which induces cell death through 2,14 Lung, NOD SCID mouse: Septic fibrinocellular inhibition of DNA synthesis. thrombi are present within the lumen of pulmonary Furthermore, genomic studies on tilivalline- arterioles. Incorporated macrophages and producing K. oxytoca in both humans and neutrophils often contain encapsulated bacilli within mice revealed a number of genes associated their cytoplasm. (HE, 400X). (Photo courtesy of: In Vivo Animal Core, Unit for Laboratory Animal 2 with virulence potential. Finally, a substrain Medicine, University of Michigan Medical School, of K. oxytoca (TNM3) has been shown to Ann Arbor, MI 48109 produce an immunosuppressive http://animalcare.umich.edu/business-services/vivo- polysaccharide, AZ9, which is associated The source of the infection is unknown, but with decreased IL4 and IFNg responses it is possible that K. oxytoca was introduced leading to an overall depressed Th2-type through human contact as this organism can 1 immune response.11,12 be spread from humans to rodents, or through environmental contamination. One In the present case, lesions were clearly major
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