Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis

Abstract

West Nile virus (WNV) is a mosquito-transmitted flavivirus that can cause debilitating encephalitis. To delineate the mechanisms behind this pathology, we studied Ccr7-deficient mice, which afforded us the capacity to study infection in mice with disrupted peripheral cellular trafficking events. The loss of Ccr7 resulted in an immediate pan-leukocytosis that remained elevated throughout the infection. This leukocytosis resulted in a significant enhancement of leukocyte accumulation within the central nervous system (CNS). Despite an excess of virus-specific T cells in the CNS, Ccr7-deficient mice had significantly higher CNS viral loads and mortality rates than wild-type animals. Mechanistically, the elevated trafficking of infected myeloid cells into the brain in Ccr7-deficient mice resulted in increased levels of WNV in the CNS, thereby effectively contributing to neuroinflammation and lowering viral clearance. Combined, our experiments suggest that during WNV infection, Ccr7 is a gatekeeper for nonspecific viral transference to the brain. IMPORTANCEIn this study, we show that Ccr7 is required for the sufficient migration of dendritic cells and T cells into the draining lymph node immediately following infection and for the restriction of leukocyte migration into the brain. Further, the severe loss of dendritic cells in the draining lymph node had no impact on viral replication in this organ, suggesting that WNV may migrate from the skin into the lymph node through another mechanism. Most importantly, we found that the loss of Ccr7 results in a significant leukocytosis, leading to hypercellularity within the CNS, where monocytes/macrophages contribute to CNS viremia, neuroinflammation, and increased mortality. Together, our data point to Ccr7 as a critical host defense restriction factor limiting neuroinflammation during acute viral infection.KEYWORDS arbovirus, cell trafficking, chemokine receptors, chemokines, hostpathogen interactions, leukocytes, neuroimmunology, viral pathogenesis W est Nile virus (WNV) is a mosquito-transmitted flavivirus that was introduced into the United States in 1999 (1). Since then, the virus has spread rapidly across the continent and has become the leading cause of arthropod-borne virus-induced encephalitis in the United States. WNV is a significant public health concern due to the unpredictable nature of annual disease outbreaks and the lack of specific therapeutics and vaccines for human use (2). In humans, WNV is transmitted through the bite of an infected mosquito. The outcome of infection ranges from asymptomatic to severe neuroinvasive disease, including meningitis, encephalitis, and/or acute flaccid paralysis (3)(4)(5)

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“…This expression profile suggests potential compensation by CCL19 for CCR7 and reflects expression profiles documented from cerebrospinal fluid from patients infected with Varicella-Zoster virus [93]. Also, studies in CCR7 deficient mice reported increased death from West Nile virus infection via over-recruitment of leukocytes and inflammation [94]. The reduced activity of CCR7 observed could make PD cells vulnerable to neuropathogens due to enhanced expression towards an inflammatory response.…”

CCR7 as a therapeutic target in Cancer

“…Chemokines' principle role is in orchestrating the inflammatory and both adaptive and innate immunological responses; and in particular, controlling migration and function of various leukocytes including eosinophils, neutrophils, and basophils as well as T and B lymphocytes [6]. More recently however, chemokines and their receptors are shown to be involved in a wider range of physiological and pathophysiological processes ranging from directing sperms movement towards the ovum [7] to asthma [8], rheumatoid arthritis [9], atherosclerosis [10], and viral infection [11][12][13][14]. In particular, many chemokine axes are shown to have a multifaceted involvement in cancer [15][16][17][18][19][20][21].…”

Monocyte subset redistribution from blood to kidneys in patients with Puumala virus caused hemorrhagic fever with renal syndrome

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