In the coming decades human space exploration is expected to move beyond low-Earth orbit. This transition involves increasing mission time and therefore an increased risk of radiation exposure from solar particle event (SPE) radiation. Acute radiation effects after exposure to SPE radiation are of prime importance due to potential mission-threatening consequences. The major objective of this study was to characterize the dose–response relationship for proton and γ radiation delivered at doses up to 2 Gy at high (0.5 Gy/min) and low (0.5 Gy/h) dose rates using white blood cell (WBC) counts as a biological end point. The results demonstrate a dose-dependent decrease in WBC counts in mice exposed to high- and low-dose-rate proton and γ radiation, suggesting that astronauts exposed to SPE-like radiation may experience a significant decrease in circulating leukocytes.

In a solar particle event (SPE), an unshielded astronaut would receive proton radiation with an energy profile that produces a highly inhomogeneous dose distribution (skin receiving a greater dose than internal organs). The novel concept of using megavoltage electron-beam radiation to more accurately reproduce both the total dose and the dose distribution of SPE protons and make meaningful RBE comparisons between protons and conventional radiation has been described previously. Here, Yucatan minipigs were used to determine the effects of a superficial, SPE-like proton dose distribution using megavoltage electrons. In these experiments, dose-dependent increases in skin pigmentation, ulceration, keratinocyte necrosis and pigment incontinence were observed. Five of 18 animals (one each exposed to 7.5 Gy and 12.5 Gy radiation and three exposed to 25 Gy radiation) developed symptomatic, radiation-associated pneumonopathy approximately 90 days postirradiation. The three animals from the highest dose group showed evidence of mycoplasmal pneumonia along with radiation pneumonitis. Moreover, delayed-type hypersensitivity was found to be altered, suggesting that superficial irradiation of the skin with ionizing radiation might cause immune dysfunction or dysregulation. In conclusion, using total doses, patterns of dose distribution, and dose rates that are compatible with potential astronaut exposure to SPE radiation, animals experienced significant toxicities that were qualitatively different from toxicities previously reported in pigs for homogeneously delivered radiation at similar doses.

Purpose The effects of radiation +/− hypogravity on immunologic function were investigated using the Partial Weight Suspension (PWS) model (Wagner et al. 2010). Materials and methods Mice were exposed to 0.5, 1, or 2 Gray (Gy) dose of gamma radiation and then placed in the PWS system for 4, 24, 48 hours, or 4 days. Spleens were excised and white blood cells were prepared for flow cytometry analyses. Results The combination of PWS + radiation (1 and 2 Gy doses only) resulted in decreased cell viability at the 24 h (~16% decrease), 48 h (~20% decrease), and 4 day (~20% decrease) time points, compared to the PWS (no radiation) and no treatment (non-suspended, non-irradiated) groups. The T lymphocyte (thymus-derived) population increased by ~10% (24 h, 48 h, and 4 day time points), while the B lymphocyte (bursal or bone marrow-derived) population decreased by ~10% (at all time points examined), when mice were exposed to PWS + radiation (2 Gy dose only), compared to the PWS or no treatment groups. T cell activation was observed in the PWS group and the 0.5 Gy +/− PWS groups at the 4 and 24 h time points, compared to the no treatment group. However, T cell activation was significantly suppressed (~85%) at the acute time points in the 2 Gy +/− PWS groups, comparable to the no treatment group. Conclusions Ionizing radiation in the absence and presence of simulated hypogravity results in acute lymphocyte dysfunction and compromised immune response.

Animal models are frequently used to assist in the determination of the long- and short-term effects of space flight. The space environment, including microgravity, can impact many physiological and immunological system parameters. It has been found that ground based models of microgravity produce changes in white blood cell counts, which negatively affects immunologic function. As part of the Center of Acute Radiation Research (CARR), we compared the acute effects on white blood cell parameters induced by the more traditionally used animal model of hindlimb unloading (HU) with a recently developed reduced weightbearing analog known as partial weight suspension (PWS). Female ICR mice were either hindlimb unloaded or placed in the PWS system at 16% quadrupedal weightbearing for 4 h, 1, 2, 7 or 10 days, at which point complete blood counts were obtained. Control animals (jacketed and non-jacketed) were exposed to identical conditions without reduced weightbearing. Results indicate that significant changes in total white blood cell (WBC), neutrophil, lymphocyte, monocyte and eosinophil counts were observed within the first 2 days of exposure to each system. These differences in blood cell counts normalized by day 7 in both systems. The results of these studies indicate that there are some statistically significant changes observed in the blood cell counts for animals exposed to both the PWS and HU simulated microgravity systems.

c Nontypeable Haemophilus influenzae (NTHi) initiates infection by colonizing the upper respiratory tract and is a common cause of localized respiratory tract disease. Previous work has established that the NTHi HMW1 and HMW2 proteins are potent adhesins that mediate efficient in vitro adherence to cultured human respiratory epithelial cells. In this study, we used a rhesus macaque model to assess the contributions of HMW1 and HMW2 to in vivo colonization. In experiments involving inoculation of individual isogenic derivatives of NTHi strain 12, the parent strain expressing both HMW1 and HMW2 and the mutant strains expressing either HMW1 or HMW2 were able to colonize more frequently than the double mutant strain lacking HMW1 and HMW2. In competition experiments, the parent strain efficiently outcompeted the double mutant lacking HMW1 and HMW2. Colonization with strains expressing HMW2 resulted in development of antibody against HMW2 in a number of the animals, demonstrating that colonization can stimulate an antibody response. In conclusion, we have established that the HMW1 and HMW2 adhesins play a major role in facilitating colonization of the upper respiratory tract of rhesus macaques, in some cases associated with stimulation of an immune response. Nontypeable Haemophilus influenzae (NTHi) is a human-specific organism that colonizes the upper respiratory tract of nearly half of all children before the age of 2 years (1-4). In the vast majority of individuals, colonization remains asymptomatic and has no adverse effects on the host. However, under the proper circumstances NTHi will spread contiguously within the respiratory tract to produce localized respiratory tract disease. NTHi is a common cause of otitis media, sinusitis, and conjunctivitis in young children and a frequent etiology of community-acquired pneumonia and exacerbations of chronic obstructive pulmonary disease in adults (5, 6). Colonization of the upper respiratory tract is an essential first step in the pathogenesis of NTHi disease, underscoring the importance of understanding the bacterial and host determinants of colonization.Adherence to respiratory epithelial cells is presumed to be an important step in the process of NTHi colonization. In earlier work, we established that the NTHi HMW1 and HMW2 proteins mediate high-level adherence to cultured human respiratory epithelial cells and are the major adhesins in 75 to 80% of NTHi isolates (7-12). HMW1 and HMW2 are highly homologous glycoproteins that are presented on the bacterial surface by the twopartner secretion system (35). Based on studies using prototypic NTHi strain 12, HMW1 and HMW2 are 71% identical and 80% similar and have maximal sequence divergence in their binding domains (13). In experiments using a panel of human epithelial cell types, HMW1 and HMW2 have different cellular binding specificities, suggesting that these two proteins interact with different host cell receptors (7,14).Although HMW1 and HMW2 have been well characterized in vitro, they have yet to be evaluated as col...