Helminth-Induced Immune Regulation: Implications for Immune Responses to Tuberculosis

Tuberculosis (TB) caused by the bacteriaMycobacterium tuberculosis (Mtb) remains a global cause of considerable morbidity and mortality [1]. One of the biggest current challenges of TB control is our incomplete understanding of what constitutes protective immunity in TBendemic areas of the world. Although close to 2,200 million people maintain the infection in a state of latency and act as a reservoir of infection, the risk factors for reactivation to active disease and subsequent transmission in these populations are poorly understood. These areas also report some of the lowest rates of efficacy of the Bacillus Calmette–Guérin (BCG) vaccine [2]. Helminth infections (soil transmitted and vector-borne) exhibit broad geographic overlap with areas of TB endemicity [3]. These complex eukaryotes have the ability to establish chronic, often asymptomatic infections and have evolved highly effective methods for subverting the immune system for their survival. Their immunomodulatory effects (as we discuss below) have been shown to extend to nonparasitic infections and vaccine responses [4, 5]. Our knowledge of how helminth-coinfection-induced immune regulation can affect TB-specific immunity and disease in an endemic area comes from three broad areas of study, with specific animal models providing supplemental evidence for particular immunologic phenomena at various stages of helminth infection. First, the effects of chronic maternal helminth infection can lead to in utero sensitization to helminth antigens [6, 7] and have the potential to affect neonatal responses to BCG vaccination [8] as well as TB-specific immunity. This has important implications, as children less than 3 years of age represent the major pediatric disease burden in endemic areas [9]. Secondly, repeated exposure to vectorand soil-transmitted helminths occurs with increasing age, leading to an age-related increase both in helminth prevalence and in the rate of acquiring TB [10, 11]. Lastly, adult subjects in endemic areas with chronic helminth infection show impaired cellular responses that may alter the responses toMtb antigens and possibly contribute to a higher incidence of active TB disease [12]. In this context, it is important to keep in mind some of the challenges to addressing these questions in a clinical setting. The proper diagnosis of active helminth infection can be challenging and is dependent on various factors such as the species being tested, intensity of infection [13] in a given area, and type of diagnostic test used. Also, polyparasitism is not uncommon, especially for intestinal helminth infections, and newer molecular diagnostic tests might provide higher sensitivity and specificity [14] compared to traditional stool-based techniques. Coinfection with HIV can also be an important confounder, especially for immunologic assessments in these populations. Finally, immunomodulation