Complement C3a Receptor (C3aR) Mediates Vascular Dysfunction, Hippocampal Pathology, and Cognitive Impairment in a Mouse Model of VCID.

Vascular contributions to cognitive impairment and dementia (VCID) secondary to chronic mild-moderate cerebral ischemia underlie a significant percentage of cases of dementia. We previously reported that either genetic deficiency of the complement C3a receptor (C3aR) or its pharmacological inhibition protects against cerebral ischemia in rodents, while others have implicated C3aR in the pathogenesis seen in rodent transgenic models of Alzheimer's disease. In the present study, we evaluated the role of complement C3a-C3aR signaling in the onset and progression of VCID. We utilized the bilateral common carotid artery stenosis (BCAS) model to induce VCID in male C57BL/6 wild-type and C3aR-knockout (C3aR-/-) mice. Cerebral blood flow (CBF) changes, hippocampal atrophy (HA), white matter degeneration (WMD), and ventricular size were assessed at 4 months post-BCAS using laser speckle contrast analysis (LSCI) and magnetic resonance imaging (MRI). Cognitive function was evaluated using the Morris water maze (MWM), and novel object recognition (NOR), immunostaining, and western blot were performed to assess the effect of genetic C3aR deletion on post-VCID outcomes. BCAS resulted in decreased CBF and increased HA, WMD, and neurovascular inflammation in WT (C57BL/6) compared to C3aR-/- (C3aR-KO) mice. Moreover, C3aR-/- mice exhibited improved cognitive function on NOR and MWM relative to WT controls. We conclude that over-activation of the C3a/C3aR axis exacerbates neurovascular inflammation leading to poor VCID outcomes which are mitigated by C3aR deletion. Future studies are warranted to dissect the role of cell-specific C3aR in VCID.

Investigating the Role of Animal Burrows on the Ecology and Distribution of Coccidioides spp. in Arizona Soils.

The lack of knowledge regarding the ecology of Coccidioides spp. makes both modeling the potential for disease outbreaks and predicting the distribution of the organism in the environment challenging. No single ecological parameter explains the biogeography of the pathogen. Previous investigations suggest an association with desert mammals, but these results should be confirmed with modern molecular techniques. Therefore, we used molecular tools to analyze soils associated with animal activity (i.e., burrows) to better define the ecology and biogeography of Coccidioides spp. in Arizona. Soils were collected from locations predicted to have favorable habitat outside of the established endemic regions to better understand the ecological niche of the organism in this state. Our central hypothesis is that soils taken from within animal burrows will have a higher abundance of Coccidioides spp. when compared to soils not directly associated with animal burrows. Our results show that there is a positive relationship with Coccidioides spp. and animal burrows. The organism was detected in two locations in northern Arizona at sites not known previously to harbor the fungus. Moreover, this fungus is able to grow on keratinized tissues (i.e., horse hair). These results provide additional evidence that there is a relationship between Coccidioides spp. and desert animals, which sheds new light on Coccidioides' ecological niche. These results also provide evidence that the geographic range of the organism may be larger than previously thought, and the concept of endemicity should be reevaluated for Coccidioides.

The mysterious desert dwellers: Coccidioides immitis and Coccidioides posadasii, causative fungal agents of coccidioidomycosis.

The genus Coccidioides consists of two species: C. immitis and C. posadasii. Prior to 2000, all disease was thought to be caused by a single species, C. immitis. The organism grows in arid to semiarid alkaline soils throughout western North America and into Central and South America. Regions in the United States, with highest prevalence of disease, include California, Arizona, and Texas. The Mexican states of Baja California, Coahuila, Sonora, and Neuvo Leon currently have the highest skin test positive results. Central America contains isolated endemic areas in Guatemala and Honduras. South America has isolated regions of high endemicity including areas of Colombia, Venezuela, Argentina, Paraguay, and Brazil. Although approximately 15,000 cases per year are reported in the United States, actual disease burden is estimated to be in the hundreds of thousands, as only California and Arizona have dedicated public health outreach, and report and track disease reliably. In this review, we survey genomics, epidemiology, ecology, and summarize aspects of disease, diagnosis, prevention, and treatment.