The helminth Schistosoma mansoni modulates the infected host’s immune system to facilitate its own survival, by producing excretory/secretory molecules that interact with a variety of the host’s cell types including those of the immune system. Herein, we characterise the S. mansoni adult male worm secretome and identify 111 proteins, including 7 vaccine candidates and several molecules with potential immunomodulatory activity. Amongst the molecules present in the secretome, a 17-19kDa protein analogous to human cyclophilin A was identified. Given the ability of cyclophilin A to modulate the immune system by regulating antigen presenting cell activity, we sought to determine whether recombinant S. mansoni Cyclophilin A (rSmCypA) is capable of modulating bone-marrow derived dendritic cell (BMDC) and T cell responses under in vitro conditions. rSmCypA was enzymatically active and able to alter the pro-inflammatory cytokine profile of LPS-activated dendritic cells. rSmCypA also modulated DC function in the induction of CD4+ T cell proliferation with a preferential expansion of Treg cells. This work demonstrates the unique protein composition of the S. mansoni male worm secretome and immunomodulatory activity of S. mansoni Cyclophilin A.

Brucella abortus is a Gram-negative bacterium that survives inside host cells as a facultative intracellular pathogen (1). It infects humans and cattle, causing a chronic inflammatory disease known as brucellosis. In humans, brucellosis symptoms include undulant fever, endocarditis, arthritis, and osteomyelitis (2). In cattle, B. abortus causes miscarriage and infertility, leading to serious economic losses (3). The host immune response to B. abortus is initiated through innate immune mechanisms that recognize bacterial components and provide the necessary signals for the induction of an adaptive immune response (4). This specific adaptive immune response, which is Th1 mediated, plays a critical role in host control of B. abortus (5). The Th1-driven immune response to B. abortus involves CD4 ϩ and CD8 ϩ T lymphocytes, macrophages, dendritic cells (DCs), and proinflammatory cytokines such as gamma interferon (IFN-␥) and interleukin-12 (IL-12) (6-9).There is a growing interest in the immunoregulatory role of lipid mediators in infectious diseases (10-12). 5-Lipoxygenase (5-LO) is an enzyme required for the biosynthesis of two important groups of lipid mediators, leukotrienes (LTs) and lipoxins (LXs), both derived from arachidonic acid. 5-LO is made in several cell types, including neutrophils, eosinophils, monocytes/macrophages, dendritic cells, mast cells, and lymphocytes (13). To produce LTs, 5-LO acts on arachidonic acid, converting it to leukotriene A 4 (LTA 4 ). LTA 4 is then converted into leukotriene B 4 (LTB 4 ) or leukotriene C 4 (LTC 4 ), molecules that are exported from the cell (14). LTs are produced at the initial steps of the acute inflammatory response and act predominantly as proinflammatory lipid mediators. LTB 4 , for example, attracts neutrophils, monocytes, and lymphocytes to the site of inflammation and induces edema formation by increasing vascular permeability and plasma leakage at the site of inflammation (15-18). In contrast to LTs, production of LXs is dependent on cell-cell interaction by a process known as transcellular biosynthesis and requires the interaction between 5-LO and 15-or 12-lipoxygenase (15-LO or 12-LO, respectively) (19). Production of LXs by 5-15-LOs begins in eosinophils, monocytes, or epithelial cells (18). The 15-LO metabolic product, 15S-hydroperoxyeicosatetraenoic acid (15S-HPETE), is released by these cells, taken up by polymorphonuclear cells or monocytes, and then processed by 5-LO into bioactive lipoxin A 4 (LXA 4 ) or lipoxin B 4 (LXB 4 ). Production of LXs by 15-12-LO occurs after arachidonic acid conversion to LTA 4 by 5-LO in leukocytes. LTA 4 is taken up by platelets and transformed to LXA 4 and LXB 4 via 12-LO activity (20). LXs act as anti-inflammatory and proresolution lipid mediators, by inhibiting both neutrophil and eosinophil transmigration into sites of infection and by promoting the noninflammatory infiltration of monocytes that is required for resolution and wound healing (21-23). LXs also stimulate macrophages to ingest and clear apoptotic neutrop...

Guanylate binding proteins (GBPs) are important effector molecules of autonomous response induced by proinflammatory stimuli, mainly IFNs. The murine GBPs clustered in chromosome 3 (GBPchr3) contains the majority of human homologous GBPs. Despite intense efforts, mycobacterial-promoted diseases are still a major public health problem. However, the combined importance of GBPchr3 during mycobacterial infection has been overlooked. This study addresses the influence of the GBPchr3 in host immunity against mycobacterial infection to elucidate the relationship between cell-intrinsic immunity and triggering of an efficient antimycobacterial immune response. Here we show that all GBPchr3 are up-regulated in lungs of mice during Mycobacterium bovis BCG infection, resembling tissue expression of IFN-. Mice deficient in GBPchr3 (GBPchr3 −/−) were more susceptible to infection, displaying diminished expression of autophagy-related genes (LC3B, ULK1, and ATG5) in lungs. Additionally, there was reduced proinflammatory cytokine production complementary to diminished numbers of myeloid cells in spleens of GBPchr3 −/−. Higher bacterial burden in GBPchr3 −/− animals correlated with increased number of tissue granulomas. Furthermore, absence of GBPchr3 hampered activation and production of TNF-and IL-12 by dendritic cells. Concerning macrophages, lack of GBPs impaired their antimicrobial function, diminishing autophagy induction and intracellular killing efficiency. In contrast, single GBP2 deficiency did not contribute to in vivo bacterial control. In conclusion, this study shows that GBPchr3 are important not only to stimulate cell-intrinsic immunity but also for inducing an efficient immune response to control mycobacterial infection in vivo.

Schistosomiasis is a parasitic disease with more than 200 million people infected worldwide. The formation of granulomas around eggs trapped in the liver is the main cause of disease morbidity. Therefore, the aim of this investigation was to characterize the immunopathological response induced by the recombinant (r) IPSE/alpha-1 egg protein in mice. Herein, we have shown that splenocytes from mice immunized with rIPSE/alpha-1 produced IFN-gamma, TNF-alpha, IL-4, IL-5 and IL-13 characterizing a mixed Th1/Th2 type of immune response. Pathological analysis of the liver revealed that there was no alteration in the number of eggs and granulomas; however, we observed an increase in granuloma area in immunized mice. Furthermore, eosinophil peroxidase assay showed that there was no alteration in the eosinophil infiltration in the liver; however, n-acetyl-beta-glucosaminidase measurement revealed an increase in macrophage activity. Despite the alteration in the profile of liver inflammatory cells in rIPSE immunized mice, the production of chemokines such as CCL2, CCL3, CCL5 and CCL11 was unaltered compared with the control group. In conclusion, IPSE/alpha-1 immunization induces a mixed Th1/Th2 type of immune response and enlargement of hepatic granuloma caused by an increased macrophage activity, but does not alter Th2 cytokines following infection.

Bacillus Calmette-Guerin (BCG) is the only FDA approved first line therapy for patients with nonmuscle invasive bladder cancer. The purpose of this study is to better understand the role of innate immune pathways involved in BCG immunotherapy against murine bladder tumor. We first characterized the immunological profile induced by the MB49 mouse urothelial carcinoma cell line. MB49 cells were not able to activate an inflammatory response (TNF-α, IL-6, CXCL-10 or IFN-β) after the stimulus with different agonists or BCG infection, unlike macrophages. Although MB49 cells are not able to induce an efficient immune response, BCG treatment could activate other cells in the tumor microenvironment (TME). We evaluated BCG intratumoral treatment in animals deficient for different innate immune molecules (STING−/−, cGAS−/−, TLR2−/−, TLR3−/−, TLR4−/−, TLR7−/−, TLR9−/−, TLR3/7/9−/−, MyD88−/−, IL-1R−/−, Caspase1/11−/−, Gasdermin-D−/− and IFNAR−/−) using the MB49 subcutaneous mouse model. Only MyD88−/− partially responded to BCG treatment compared to wild type (WT) mice, suggesting a role played by this adaptor molecule. Additionally, BCG intratumoral treatment regulates cellular infiltrate in TME with an increase of inflammatory macrophages, neutrophils and CD8+ T lymphocytes, suggesting an immune response activation that favors tumor remission in WT mice but not in MyD88−/−. The experiments using MB49 cells infected with BCG and co-cultured with macrophages also demonstrated that MyD88 is essential for an efficient immune response. Our data suggests that BCG immunotherapy depends partially on the MyD88-related innate immune pathway.

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Transplacental transmission of Zika virus (ZIKV) during early pregnancy may lead to several neurological alterations, known as congenital Zika syndrome. We have previously shown that intravaginal infection of immunocompetent dams with ZIKV during the early stage of pregnancy triggers neuroinflammation in fetuses, characterized by increased brain expression of inflammatory factors, including IL-6, IL-18, CCL2, CXCL1, and CXCL10. The present study sought to understand the long-term consequences of these early cerebral alterations. For that, pregnant FVB/NJ immunocompetent females were infected intravaginally on the gestational day (GD) 4.5 and experiments were performed when offspring reached between 4 to 5 months of age. The exposure to ZIKV promoted significant neuronal cell loss detected in the CA1 region of the hippocampus of adult mice. However, only females showed reduced expression levels of brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD95), and syntaxin-1A, which are important genes related to neuronal function and synaptic plasticity. Moreover, the protein levels of the pre- and postsynaptic markers, SNAP25 and PSD95, respectively, were decreased exclusively in ZIKV-exposed female mice, indicating that ZIKV exposure in utero induces synaptic loss. Additionally, only females exposed to ZIKV showed risk-taking behavior and hippocampal-dependent spatial memory deficit. Together, these results demonstrate that intravaginal infection of mice on GD4.5 induces neurological alterations in the offspring detectable in their adulthood and that female mice, rather than male mice, are more susceptible to ZIKV-induced neurobehavioral alterations. Summary Statement In utero exposure to ZIKV leads to decreased number of neurons in adult mice. Female mice exposed to ZIKV in utero exhibit lower levels of BDNF, a decrease in synaptic markers, memory deficits, and risk-taking behavior during adulthood.

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