Mycobacterium kansasii Isolated from Tuberculinpositive Rhesus Macaques (Macaca mulatta) in the Absence of Disease.

Mycobacterial infections are of primary health concern in NHP colonies in biomedical research. NHP are constantly monitored and screened for Mycobacterium spp. We report 6 Chinese-origin rhesus macaques infected with Mycobacterium kansasii that exhibited positive tuberculin skin tests in the absence of disease. Two of these macaques were being used for research purposes; the remaining 4 macaques were residing at the contract quarantine company. Histopathology and acid-fast staining of fixed tissues from all macaques showed that all were free of disease. Thoracic radiographs were negative for any signs of disease or infection. Samples from bronchial lavage and tissues including lung, spleen, hilar and mesenteric lymph nodes tested negative by PCR assay for Mycobacterium spp. One of the research macaques tested culture-positive for M. kansasii and a poorly characterized M. avium complex organism. One macaque from the contract quarantine facility tested culture positive for M. kansasii. Genomic testing and target gene RNA expression analysis of the 2 M. kansasii isolates were performed to evaluate possible kinship and affected genes that might contribute to susceptibility to mycobacterial infection. Genotyping of the 2 isolates revealed 2 genetically distinct strains (strains 1 and 4). The presence of positive tuberculin skin tests in the absence of disease raises serious concerns regarding diagnostic methods used for infected NHP.

Decreased necrotizing fasciitis capacity caused by a single nucleotide mutation that alters a multiple gene virulence axis.

Single-nucleotide changes are the most common cause of natural genetic variation among members of the same species, but there is remarkably little information bearing on how they alter bacterial virulence. We recently discovered a single-nucleotide mutation in the group A Streptococcus genome that is epidemiologically associated with decreased human necrotizing fasciitis ("flesh-eating disease"). Working from this clinical observation, we find that wild-type mtsR function is required for group A Streptococcus to cause necrotizing fasciitis in mice and nonhuman primates. Expression microarray analysis revealed that mtsR inactivation results in overexpression of PrsA, a chaperonin involved in posttranslational maturation of SpeB, an extracellular cysteine protease. Isogenic mutant strains that overexpress prsA or lack speB had decreased secreted protease activity in vivo and recapitulated the necrotizing fasciitis-negative phenotype of the DeltamtsR mutant strain in mice and monkeys. mtsR inactivation results in increased PrsA expression, which in turn causes decreased SpeB secreted protease activity and reduced necrotizing fasciitis capacity. Thus, a naturally occurring single-nucleotide mutation dramatically alters virulence by dysregulating a multiple gene virulence axis. Our discovery has broad implications for the confluence of population genomics and molecular pathogenesis research.

Disruption of the NAD(P)H:quinone oxidoreductase 1 (NQO1) gene in mice causes myelogenous hyperplasia.

NAD(P)H:quinone oxidoreductase1 (NQO1) is a cytosolic protein that reduces and detoxifies quinones and their derivatives, thus protecting cells against redox cycling and oxidative stress. Disruption of the NQO1 gene in mice caused myeloid hyperplasia of bone marrow and highly significant increases in blood neutrophils, eosinophils, and basophils. NQO1-null mice also showed a decrease in lymphocytes and WBCs as compared with wild-type mice. Various techniques also demonstrated an increase in megakaryocytes without an increase in blood platelets. Histological analysis of liver, kidney, spleen, and thymus did not demonstrate a difference between wild-type and NQO1-null mice or a sign of infection. Blood cultures and urine analysis also did not demonstrate any sign of infection in NQO1-null and wild-type mice. Additional analysis of the bone marrow from NQO1-null mice revealed that loss of NQO1 alters the intracellular redox status because of accumulation of NAD(P)H, cofactors for NQO1. This causes a reduction in the levels of pyridine nucleotides and tumor suppressor proteins p53 and p73, and a decrease in apoptosis. The decrease in apoptosis causes myelogenous hyperplasia in NQO1-null mice. These results demonstrate that NQO1 acts as an endogenous factor in the protection against myelogenous hyperplasia. This is significant because 2-4% of human individuals without known abnormalities, and >25% of individuals with benzene poisoning and acute myelogenic leukemia are homozygous for a mutant allele (P187S) of NQO1 and lack NQO1 protein/activity.

Spontaneous Renal Cell Carcinoma in a New Zealand White Rabbit.

The incidence of primary renal neoplasia in animals is quite low. Carcinomas are the most common primary renal tumors of dogs, cattle, and sheep. Among rabbit tumors, only uterine adenocarcinomas occur more frequently than do embryonal nephromas. However, spontaneous renal cell carcinomas in laboratory rabbits have only been reported once previously. We here report a second occurrence of a renal cell carcinoma in the laboratory rabbit.