Caudell, D. L. | bioRxiv Science

bioRxiv2020

Diastolic Dysfunction Accompanies Alterations in Myocardial Structure, Cellular Composition and Macrophage Polarization in Survivors of Ionizing Radiation Exposure

RationaleRadiation induced heart disease (RIHD) is a significant delayed/late effect of ionizing radiation exposure. ObjectiveTo determine the cardiac effects of total body irradiation (TBI) in male rhesus macaques, a translational non-human primate (NHP) model. Methods and ResultsEchocardiography was performed on survivors of a single dose (6.4-8.5 Gy) of TBI (n=34) and non-irradiated controls (n=26) divided into longer (LT IRR) and shorter term (ST IRR) survivors and controls to assess the effects of time since TBI on phenotypes. LT IRR had increased Doppler transmitral early filling velocities (E), decreased early mitral annular descent velocities (e), and higher E/e ratio compared to LT CTL (all p[≤]0.05), indicating left ventricular (LV) diastolic dysfunction. Echocardiographic stroke volume, cardiac output, and end-diastolic and systolic volumes were also lower in LT IRR than controls (all p [≤] 0.05). ST IRR had similar alterations in LV diastolic function but not in cardiac volumetric measures. Analyses of LV, interventricular septum (IVS), and right ventricle (RV) myocardium from deceased irradiated animals (n=17) exposed to a single dose (6.9-8.05 Gy) TBI and non-irradiated controls (n=12) showed that IRR animals had decreased LV and IVS capillary density, and increased LV fibrosis, pan-cardiac fibroblast and macrophage staining, LV and IVS M2 macrophages, and pan-cardiac M1 macrophages (all p<0.05). While M2 predominated over M1 macrophages in both groups, M1 showed greater increases than M2 in IRR. ConclusionsLV diastolic dysfunction due to radiation exposure may be due to a combination of capillary rarefication, activation and expansion of fibroblasts, and increased accumulation of both pro-fibrotic and pro-inflammatory macrophages, all of which lead to increased myocardial stiffness due to fibrosis. Collectively, these findings provide insights into the delayed effects of acute ionizing radiation exposure and suggest that therapies targeting macrophage regulation of fibrosis may mitigate radiation induced heart disease.

pathology↗

bioRxiv2020

An Animal Model to Study Klebsiella pneumoniae Gastro-Intestinal Colonization and Host-to-Host Transmission

An important yet poorly understood facet in the life cycle of a successful pathogen is the host-to-host transmission. Hospital-acquired infections (HAI) resulting from the transmission of drug-resistant pathogens affect hundreds of millions of patients worldwide. Klebsiella pneumoniae (Kpn), a gram-negative bacterium, is notorious for causing HAI, with many of these infections difficult to treat as Kpn has become multi-drug resistant. Epidemiological studies suggest that Kpn host-to-host transmission requires close contact and generally occurs through the fecal-oral route. Herein, we describe a murine model that can be utilized to study mucosal (oropharynx and gastrointestinal [GI]) colonization, shedding within feces, and transmission of Kpn through the fecal-oral route. Using an oral route of inoculation, and fecal shedding as a marker for GI colonization, we show that Kpn can asymptomatically colonize the GI tract of immunocompetent mice, and modifies the host GI microbiota. Colonization density within the GI tract and levels of shedding in the feces differed among the clinical isolates tested. A hypervirulent Kpn isolate was able to translocate from the GI tract and cause hepatic infection that mimicked the route of human infection. Expression of the capsule was required for colonization and, in turn, robust shedding. Furthermore, Kpn carrier mice were able to transmit to uninfected cohabitating mice. Lastly, treatment with antibiotics led to changes in the host microbiota and development of a transient super-shedder phenotype, which enhanced transmission efficiency. Thus, this model can be used to determine the contribution of host and bacterial factors towards Kpn dissemination.

microbiology↗