Progressive multifocal leukoencephalopathy (PML) is a rare, but serious, complication encountered in patients treated with a select number of disease-modifying therapies (DMTs) utilized in treating multiple sclerosis (MS). PML results from a viral infection in the brain for which the only demonstrated effective therapy is restoring the perturbed immune system-typically achieved in the patient with MS by removing the offending therapeutic agent or, in the case of HIV-associated PML, treatment with highly active antiretroviral therapies. Other therapies for PML remain either ineffective or experimental. Significant work to understand the virus and host interaction has been undertaken, but lack of an animal model for the disorder has significantly hindered progress, especially with respect to development of treatments. Strategies to limit risk of PML with natalizumab, a drug that carries a uniquely high risk for the development of the disorder, have been developed. Identifying factors such as positive JC virus antibody status that increase PML risk, at least in theory, should decrease the incidence rate of the disease. Whether other risk factors for PML can be identified and validated or unique strategies should be employed in association with other DMTs that predispose to PML and whether this has a salutary effect on outcome remains to be demonstrated. Identifying PML early, then promptly eliminating drug in the case of natalizumab-associated PML has demonstrated better outcomes, but the complication of PML continues to carry significant morbidity and mortality. While the scientific community has yet to identify targeted therapy with proven efficacy against JCV or PML there are several candidates being studied.

Saliva from the mosquito vector of flaviviruses is capable of changing the local immune environment, leading to an increase in flavivirus-susceptible cells at the infected bite site. In addition, an antibody response to specific salivary gland (SG) components changes the pathogenesis of flaviviruses in human populations. To investigate whether antigenic SG proteins are capable of enhancing infection with Zika virus (ZIKV), a reemerging flavivirus primarily transmitted by the Aedes aegypti mosquito, we screened for antigenic SG proteins using a yeast display library and demonstrate that a previously undescribed SG protein we term neutrophil stimulating factor 1 (NeSt1) activates primary mouse neutrophils ex vivo. Passive immunization against NeSt1 decreases pro-interleukin-1␤ and CXCL2 expression, prevents macrophages from infiltrating the bite site, protects susceptible IFNAR Ϫ/Ϫ IFNGR -/-(AG129) mice from early ZIKV replication, and ameliorates virus-induced pathogenesis. These findings indicate that NeSt1 stimulates neutrophils at the mosquito bite site to change the immune microenvironment, allowing a higher level of early viral replication and enhancing ZIKV pathogenesis. IMPORTANCE When a Zika virus-infected mosquito bites a person, mosquito saliva is injected into the skin along with the virus. Molecules in this saliva can make virus infection more severe by changing the immune system to make the skin a better place for the virus to replicate. We identified a molecule that activates immune cells, called neutrophils, to recruit other immune cells, called macrophages, that the virus can infect. We named this molecule neutrophil-stimulating factor 1 (NeSt1). When we used antibodies to block NeSt1 in mice and then allowed Zika virus-infected mosquitoes to feed on these mice, they survived much better than mice that do not have antibodies against NeSt1. These findings give us more information about how mosquito saliva enhances virus infection, and it is possible that a vaccine against NeSt1 might protect people against severe Zika virus infection.

The interface of multiple sclerosis (MS) and infection occurs on several levels. First, infectious disease has been postulated as a potential trigger, if not cause, of MS. Second, exacerbation of MS has been well-documented as a consequence of infection, and, lastly, infectious diseases have been recognized as a complication of the therapies currently employed in the treatment of MS. MS is a disease in which immune dysregulation is a key component. Examination of central nervous system (CNS) tissue of people affected by MS demonstrates immune cell infiltration, activation and inflammation. Therapies that alter the immune response have demonstrated efficacy in reducing relapse rates and evidence of brain inflammation on magnetic resonance imaging (MRI). Despite the altered immune response in MS, there is a lack of evidence that these patients are at increased risk of infectious disease in the absence of treatment or debility. Links between infections and disease-modifying therapies (DMTs) used in MS will be discussed in this review, as well as estimates of occurrence and ways to potentially minimize these risks. We address infection in MS in a comprehensive fashion, including (1) the impact of infections on relapse rates in patients with MS; (2) a review of available infection data from pivotal trials and postmarketing studies for the approved and experimental DMTs, including frequency, types and severity of infections; and (3) relevant risk minimization strategies, particularly as they pertain to progressive multifocal leukoencephalopathy (PML).

SummaryThe TAM receptor, Axl, has been implicated as a candidate entry receptor for Zika virus (ZIKV) infection but has been shown as inessential for virus infection in mice. To probe the role of Axl in murine ZIKV infection, we developed a mouse model lacking the Axl receptor and the interferon alpha/beta receptor (Ifnar−/−Axl−/−), conferring susceptibility to ZIKV. This model validated that Axl is not required for murine ZIKV infection and that mice lacking Axl are resistant to ZIKV pathogenesis. This resistance correlates to lower pro-interleukin-1β production and less apoptosis in microglia of ZIKV-infected mice. This apoptosis occurs through both intrinsic (caspase 9) and extrinsic (caspase 8) manners, and is age dependent, as younger Axl-deficient mice are susceptible to ZIKV pathogenesis. These findings suggest that Axl plays an important role in pathogenesis in the brain during ZIKV infection and indicates a potential role for Axl inhibitors as therapeutics during viral infection.

A comprehensive understanding of natalizumab-associated PML is illustrative of the potential pathogenic effects of immunomodulatory agents that lead to infectious complications, as well as the recognition and potential treatment strategies of these complications. The current knowledge of immunotherapy-associated PML incidence, clinical and radiographic features, and management are discussed in detail in this article. Increased risk of herpetic and other infectious complications has also been encountered with immunomodulation. Strategies in relation to minimizing risk and decreasing chances of encountering infectious complications associated with the use of such therapies, including those related to PML, tuberculosis, herpes simplex virus, and varicella-zoster virus, are highlighted.