Chemotactic and Inflammatory Responses in the Liver and Brain Are Associated with Pathogenesis of Rift Valley Fever Virus Infection in the Mouse

Rift Valley fever virus (RVFV) is a major human and animal pathogen associated with severe disease including hemorrhagic fever or encephalitis. RVFV is endemic to parts of Africa and the Arabian Peninsula, but there is significant concern regarding its introduction into non-endemic regions and the potentially devastating effect to livestock populations with concurrent infections of humans. To date, there is little detailed data directly comparing the host response to infection with wild-type or vaccine strains of RVFV and correlation with viral pathogenesis. Here we characterized clinical and systemic immune responses to infection with wild-type strain ZH501 or IND vaccine strain MP-12 in the C57BL/6 mouse. Animals infected with live-attenuated MP-12 survived productive viral infection with little evidence of clinical disease and minimal cytokine response in evaluated tissues. In contrast, ZH501 infection was lethal, caused depletion of lymphocytes and platelets and elicited a strong, systemic cytokine response which correlated with high virus titers and significant tissue pathology. Lymphopenia and platelet depletion were indicators of disease onset with indications of lymphocyte recovery correlating with increases in G-CSF production. RVFV is hepatotropic and in these studies significant clinical and histological data supported these findings; however, significant evidence of a pro-inflammatory response in the liver was not apparent. Rather, viral infection resulted in a chemokine response indicating infiltration of immunoreactive cells, such as neutrophils, which was supported by histological data. In brains of ZH501 infected mice, a significant chemokine and pro-inflammatory cytokine response was evident, but with little pathology indicating meningoencephalitis. These data suggest that RVFV pathogenesis in mice is associated with a loss of liver function due to liver necrosis and hepatitis yet the long-term course of disease for those that might survive the initial hepatitis is neurologic in nature which is supported by observations of human disease and the BALB/c mouse model

Liver function enzymes.

<p>Alanine aminotransferase (ALT), glucose, and total bilirubin concentrations in the serum of mock (A), MP-12 (B) and ZH501 (C) infected mice. The first row provides serum ALT concentrations, the second row glucose concentrations and the third total bilirubin concentrations. Each symbol represents an individual mouse. There were five mice in each group, except at 96 hpi where only three animals had survived until this point of the study. The horizontal bar represents the mean of the mice for that group. Please note that the maximum for the Y-axis in (C)-ALT is 2000 U/L rather than 150 U/L as in (A) and (B) ALT graphs.</p

Mouse daily weight and temperature.

<p>Daily weight (g) and temperature (°C) of mock-infected C57BL/6 mice and mice infected with either MP-12 or ZH501.</p

IFN-β concentration following infection.

<p>IFN-β concentration in the (A) liver, (B) spleen, and (C) brain in mice after infection. The first row represents mock infected mice, the second row represents MP-12 infected mice, and the third is ZH501 infected mice. Each symbol represents an individual mouse. There were five mice in each group with the exception of the 96 time-point for ZH501 when only three animals were surviving. The horizontal bar represents the mean of the mice for each group. Brackets indicate that the average value for ZH501 infected animals is significantly different from both mock and MP-12 infected animals.</p

Viral Titers.

<p>Viral titers in the serum, liver, spleen, and brain after infection with (A) MP-12 or (B) ZH501. Each point with the exception of 96 hpi in the ZH501 graph represents the mean virus titer of five mice. The 96 hpi points in the ZH501 graph represent only the 3 mice that survived until that point. Error bars for the standard deviation were removed for clarity. (C) Immunohistochemical staining for RVFV antigen in liver from a ZH501 infected mouse at 60 hpi. Intracytoplasmic viral antigen is depicted by brown staining, 10×. (D) Immunohistochemical stain of liver from a ZH501 infected mouse at 84 hpi. Intracytoplasmic viral antigen is depicted by brown staining, 20×. (E) Immunohistochemical stain of spleen for RVFV antigen from a ZH501 infected mouse at 84 hpi. The red pulp sinusoids contain numerous cells with cytoplasmic brown, granular material depicting viral antigen. There are no viral antigen positive cells in the lymphoid follicle. Note the increased lymphocytolysis depicted by pyknotic nuclei and cellular fragments, 20×. (F) Brain from a ZH501 infected animal at 84 hpi with no pathologic changes, H&E 2.5×.</p

Liver and spleen pathology.

<p>(A) Liver from a mock-infected mouse at 84 hpi. The liver is essentially normal H&E 20×. (B) Liver from an MP-12 infected mouse at 84 hpi. The random, small microgranulomas composed of individually-necrotic hepatocytes surrounded by small numbers of neutrophils and mononuclear cells are unrelated to the study, H&E 20×. (C) Liver from a ZH501 infected mouse at 84 hpi, showing piecemeal hepatocyte necrosis (white arrowhead), hepatocellular intranuclear eosinophilic inclusions (white arrow). Note the presence of neutrophils (black arrow) within foci of necrosis, H&E stain 40×. (D) Spleen from a mock-infected mouse at 84 hpi. The spleen is essentially normal, H&E 20×. (E) Spleen from an MP-12 infected mouse at 84 hpi. The spleen is essentially normal, H&E 20×. (F) Spleen from a ZH501 infected mouse at 84 hpi with moderate amounts of necrotic cellular debris and macrophages containing hemosiderin (brown pigment) within red pulp sinusoids, H&E 10×.</p

Multi-laboratory compilation of atmospheric carbon dioxide data for the period 1957-2019; obspack_co2_1_GLOBALVIEWplus_v6.0_2020-09-11

A full list of all creators for this product can be found at www.esrl.noaa.gov/gmd/ccgg/obspack/providerlist/obspack_co2_1_GLOBALVIEWplus_v6.0_2020-09-11.html. This product is constructed using the Observation Package (ObsPack) framework [Masarie et al., 2014; www.earth-syst-sci-data.net/6/375/2014/]. The framework is designed to bring together atmospheric greenhouse gas (GHG) observations from a variety of sampling platforms, prepare them with specific applications in mind, and package and distribute them in a self-consistent and well-documented product. ObsPack products are intended to support GHG budget studies and represent a new generation of cooperative value-added GHG data products. This product includes 471 atmospheric carbon dioxide datasets derived from observations made by 54 laboratories from 21 countries. Data for the period 1957-2019 (where available) are included

Multi-laboratory compilation of atmospheric carbon dioxide data for the period 1957-2020; obspack_co2_1_GLOBALVIEWplus_v7.0_2021-08-18

This product is constructed using the Observation Package (ObsPack) framework [Masarie et al., 2014; www.earth-syst-sci-data.net/6/375/2014/]. The framework is designed to bring together atmospheric greenhouse gas (GHG) observations from a variety of sampling platforms, prepare them with specific applications in mind, and package and distribute them in a self-consistent and well-documented product. ObsPack products are intended to support GHG budget studies and represent a new generation of cooperative value-added GHG data products. This product includes 524 atmospheric carbon dioxide datasets derived from observations made by 63 laboratories from 21 countries. Data for the period 1957-2020 (where available) are included

Multi-laboratory compilation of atmospheric carbon dioxide data for the period 1957-2020 [Dataset]

This product is constructed using the Observation Package (ObsPack) framework [Masarie et al., 2014; www.earth-syst-sci-data.net/6/375/2014/]. The framework is designed to bring together atmospheric greenhouse gas (GHG) observations from a variety of sampling platforms, prepare them with specific applications in mind, and package and distribute them in a self-consistent and well-documented product. ObsPack products are intended to support GHG budget studies and represent a new generation of cooperative value-added GHG data products. This product includes 524 atmospheric carbon dioxide datasets derived from observations made by 63 laboratories from 21 countries. Data for the period 1957-2020 (where available) are included