Disruption of Aldehyde Dehydrogenase 2 protects against bacterial infection.

The ALDH2*2 (rs671) allele is one of the most common genetic mutations in humans, yet the positive evolutionary selective pressure to maintain this mutation is unknown, despite its association with adverse health outcomes. ALDH2 is responsible for the detoxification of metabolically produced aldehydes, including lipid-peroxidation end products derived from inflammation. Here, we demonstrate that host-derived aldehydes 4-hydroxynonenal (4HNE), malondialdehyde (MDA), and formaldehyde (FA), all of which are metabolized by ALDH2, are directly toxic to the bacterial pathogens Mycobacterium tuberculosis and Francisella tularensis at physiological levels. We find that Aldh2 expression in macrophages is decreased upon immune stimulation, and that bone marrow-derived macrophages from Aldh2 -/- mice contain elevated aldehydes relative to wild-type mice. Macrophages deficient for Aldh2 exhibited enhanced control of Francisella infection. Finally , mice lacking Aldh2 demonstrated increased resistance to pulmonary infection by M. tuberculosis , including in a hypersusceptible model of tuberculosis, and were also resistant to Francisella infection. We hypothesize that the absence of ALDH2 contributes to the host's ability to control infection by pathogens such as M. tuberculosis and F. tularensis , and that host-derived aldehydes act as antimicrobial factors during intracellular bacterial infections. One sentence summary: Aldehydes produced by host cells contribute to the control of bacterial infections.

In vivo and in vitro immune responses against Francisella tularensis vaccines are comparable among Fischer 344 rat substrains.

Identifying suitable animal models and standardizing preclinical methods are important for the generation, characterization, and development of new vaccines, including those against Francisella tularensis. Non-human primates represent an important animal model to evaluate tularemia vaccine efficacy, and the use of correlates of vaccine-induced protection may facilitate bridging immune responses from non-human primates to people. However, among small animals, Fischer 344 rats represent a valuable resource for initial studies to evaluate immune responses, to identify correlates of protection, and to screen novel vaccines. In this study, we performed a comparative analysis of three Fischer rat substrains to determine potential differences in immune responses, to evaluate methods used to quantify potential correlates of protection, and to evaluate protection after vaccination. To this end, we took advantage of data previously generated using one of the rat substrains by evaluating two live vaccines, LVS and F. tularensis SchuS4-ΔclpB (ΔclpB). We compared immune responses after primary vaccination, adaptive immune responses upon re-stimulation of leukocytes in vitro, and sensitivity to aerosol challenge. Despite some detectable differences, the results highlight the similarity of immune responses to tularemia vaccines and challenge outcomes between the three substrains, indicating that all offer acceptable and comparable approaches as animal models to study Francisella infection and immunity.

Frequency and Geographic Distribution of Borrelia miyamotoi, Borrelia burgdorferi, and Babesia microti Infections in New England Residents.

BACKGROUND: Borrelia miyamotoi is a relapsing fever spirochete that relatively recently has been reported to infect humans. It causes an acute undifferentiated febrile illness that can include meningoencephalitis and relapsing fever. Like Borrelia burgdorferi, it is transmitted by Ixodes scapularis ticks in the northeastern United States and by Ixodes pacificus ticks in the western United States. Despite reports of clinical cases from North America, Europe, and Asia, the prevalence, geographic range, and pattern of expansion of human B. miyamotoi infection are uncertain. To better understand these characteristics of B. miyamotoi in relation to other tickborne infections, we carried out a cross-sectional seroprevalence study across New England that surveyed B. miyamotoi, B. burgdorferi, and Babesia microti infections. METHODS: We measured specific antibodies against B. miyamotoi, B. burgdorferi, and B. microti among individuals living in 5 New England states in 2018. RESULTS: Analysis of 1153 serum samples collected at 11 catchment sites showed that the average seroprevalence for B. miyamotoi was 2.8% (range, 0.6%-5.2%), which was less than that of B. burgdorferi (11.0%; range, 6.8%-15.6%) and B. microti (10.0%; range, 6.5%-13.6%). Antibody screening within county residence in New England showed varying levels of seroprevalence for these pathogens but did not reveal a vectoral geographical pattern of distribution. CONCLUSIONS: Human infections caused by B. miyamotoi, B. burgdorferi, and B. microti are widespread with varying prevalence throughout New England.