Distinct Roles for MyD88 and Toll-Like Receptor 2 during Leishmania braziliensis Infection in Mice

Paul

The Journal of Immunology

et al. 2015

Infection with antimony-resistant Leishmania donovani (SbRLD) induces aggressive pathology in the mammalian hosts as compared with ones with antimony-sensitive L. donovani (SbSLD) infection. SbRLD, but not SbSLD, interacts with TLR2/TLR6 to induce IL-10 by exploiting p50/c-Rel subunits of NF-κB in infected macrophages (Mϕs). Most of the TLRs exploit the universal adaptor protein MyD88 to activate NF-κB. We now show that infection of Mϕs from MyD88−/− mice with SbRLD gave rise to significantly higher intracellular parasite number coupled with elevated IL-10/IL-12 ratio in the culture supernatant as compared with infection in wild type (WT) Mϕs. Τhese attributes were not seen with SbSLD in similar experiments. Further, SbRLD infection upregulated miR-466i, which binds with 3′-untranslated region, leading to the downregulation of MyD88. Infection of MyD88−/− Mϕ or IL-12−/− Mϕ with SbRLD induced IL-10 surge at 4 h, whereas the same in WT Mϕ started from 12 h. Thus, absence of IL-12 in MyD88−/− mice favored early binding of NF-κB subunits to the IL-10 promoter, resulting in IL-10 surge. Infection of MyD88−/− mice with SbRLD showed significantly higher organ parasites coupled with ill-defined and immature hepatic granulomas, whereas in WT mice there were less organ parasites and the granulomas were well defined. From the survival kinetics it was observed that SbRLD-infected MyD88−/− mice died by 60 d postinfection, whereas the WT mice continued to survive. Our results demonstrate that SbRLD has evolved a unique strategy to evade host antileishmanial immune repertoire by manipulating host MyD88 to its advantage.

Section: Discussionsupporting

confidence: 54%

Section: Infection Of Myd88mentioning

confidence: 99%

Section: Infection Of Myd88mentioning

confidence: 99%

See 1 more Smart Citation

Antimony-ResistantLeishmania donovaniExploits miR-466i To Deactivate Host MyD88 for Regulating IL-10/IL-12 Levels during Early Hours of Infection

Paul

The Journal of Immunology

et al. 2015

“…In contrast, TLR2 Ϫ/Ϫ mice were able to control the infection and produced more inflammatory cytokines than their WT counterparts (62). This is intriguing as MyD88 is a primary adaptor molecule involved in downstream signaling originating from TLR2.…”

Section: Discussionmentioning

confidence: 72%

Increased Disease Severity of Parasite-Infected TLR2^−/−Mice Is Correlated with Decreased Central Nervous System Inflammation and Reduced Numbers of Cells with Alternatively Activated Macrophage Phenotypes in a Murine Model of Neurocysticercosis

et al. 2011

In a murine model for neurocysticercosis (NCC), intracranial inoculation of the helminth parasite Mesocestoides corti induces multiple Toll-like receptors (TLRs), among which TLR2 is upregulated first and to a relatively high extent. Here, we report that TLR2 ؊/؊ mice displayed significantly increased susceptibility to parasite infection accompanied by increased numbers of parasites in the brain parenchyma compared to infection in wild-type (WT) mice. This coincided with an increased display of microglial nodule formations and greater neuropathology than in the WT. Parasite-infected TLR2 ؊/؊ brains exhibited a scarcity of lymphocytic cuffing and displayed reduced numbers of infiltrating leukocytes. Neurocysticercosis (NCC) is a disease of the central nervous system (CNS) caused by the metacestode of the tapeworm Taenia solium (T. solium). This is the most common parasitic disease of the CNS and is a major cause of acquired epilepsy in adults (32,57,63). In humans, T. solium exhibits a biphasic life cycle in which the infection manifests in a long asymptomatic phase during which the parasite stays dormant in the form of a cyst with no detectable inflammatory response surrounding the parasite. A symptomatic episode may follow this asymptomatic phase which rapidly leads to convolutions, cranial hypertension, and cognitive disorders (64, 65). The type and severity of symptoms depend on size, number, and anatomical location of the parasites in addition to the intensity of the immune response. The immune response in the CNS of symptomatic patients consists of an overt Th1 phenotype (53) or a mixed Th1, Th2, and Th3 phenotype, depending upon the absence or presence of granuloma formation (52). However, the appropriate immune responses required and effector mechanisms involved in restricting parasite growth and controlling disease severity in NCC are still not clear.Due to the absence of a classically defined lymphatic system, innate immune responses appear to be key elements in promoting immune responses in the CNS. Recent studies have demonstrated the critical role played by the Toll-like receptor (TLR) family of proteins in host innate immunity (24). Once engaged, most TLRs signal through a common pathway involving MyD88 (55) that leads to the downstream activation of the NF-B and mitogen-activated protein kinase (MAPK) pathways inducing a Th1 proinflammatory response (35). Nevertheless, emerging evidence indicates that TLRs can elicit antiinflammatory regulatory T (Treg) cells and Th2-associated responses as well as the induction of alternatively activated macrophages (AAMs) (15,16,49,51). This suggests a larger role for TLRs in immune regulatory mechanisms involved in various clinical settings. However, the functions of TLRs in nervous system parasitic diseases, including NCC, are only beginning to emerge (17,39,56,66,67).In a murine model for NCC, we have previously shown that intracranial (i.c.) infection of mice with Mesocestoides corti metacestodes results in differential expression of TLRs (36,40). Among all t...

The Journal of Immunology

“…Lipophosphoglycan-TLR2 interaction diminishes the antileishmanial response by reducing TLR9 expression (11). By contrast, TLR2-deficient mice on a resistant C57BL/6 background and the wild-type controls are equally resistant to Leishmania braziliensis infection (12), suggesting that TLR2 may not play a role in Leishmania infection. In contrast, as IL-10 and IL-12 play significant roles in L. major infection (13) and as stimulation of Leishmania donovani-infected human monocyte cell line-derived macrophages with Pam 3 CSK 4 -a TLR1-TLR2 ligandproduces more IL-10, but less IL-12 (14), TLR2 is implied in the control of Leishmania infection.…”

mentioning

confidence: 98%

Pegylated Bisacycloxypropylcysteine, a Diacylated Lipopeptide Ligand of TLR6, Plays a Host-Protective Role against Experimental Leishmania major Infection

Pandey

Chandel

Srivastava

et al. 2014

TLRs recognize pathogen-expressed Ags and elicit host-protective immune response. Although TLR2 forms heterodimers with TLR1 or TLR6, recognizing different ligands, differences in the functions of these heterodimers remain unknown. In this study, we report that in Leishmania major-infected macrophages, the expression of TLR1 and TLR2, but not TLR6, increased; TLR2–TLR2 association increased, but TLR2–TLR6 association diminished. Lentivirus-expressed TLR1–short hairpin RNA (shRNA) or TLR2–shRNA administration reduced, but TLR6–shRNA increased L. major infection in BALB/c mice. Corroboratively, Pam3CSK4 (TLR1–TLR2 ligand) and peptidoglycan (TLR2 ligand) increased L. major infection but reduced TLR9 expression, whereas pegylated bisacycloxypropylcysteine (BPPcysMPEG; TLR2–TLR6 ligand) reduced L. major number in L. major-infected macrophages, accompanied by increased TLR9 expression, higher IL-12 production, and inducible NO synthase expression. Whereas MyD88, Toll/IL-1R adaptor protein, and TNFR-α–associated factor 6 recruitments to TLR2 were not different in Pam3CSK4-, peptidoglycan-, or BPPcysMPEG-treated macrophages, only BPPcysMPEG enhanced p38MAPK and activating transcription factor 2 activation. BPPcysMPEG conferred antileishmanial functions to L. major-infected BALB/c-derived T cells in a macrophage–T cell coculture and in BALB/c mice; the protection was TLR6 dependent and IL-12 dependent, and it was accompanied by reduced regulatory T cell number. BPPcysMPEG administration during the priming with fixed L. major protected BALB/c mice against challenge L. major infection; the protection was accompanied by low IL-4 and IL-10, but high IFN-γ productions and reduced regulatory T cells. Thus, BPPcysMPEG, a novel diacylated lipopeptide ligand for TLR2–TLR6 heterodimer, induces IL-12–dependent, inducible NO synthase–dependent, T-reg–sensitive antileishmanial protection. The data reveal a novel dimerization partner-dependent duality in TLR2 function.