Immunomodulatory effects of Rhipicephalus haemaphysaloides serpin RHS2 on host immune responses

Abstract

Background Rhipicephalus haemaphysaloides is a widespread tick species in China and other South East Asian countries, where it is the vector of many pathogens. The objective of this study was to study the role of serpin (serine protease inhibitor) during the tick-host interaction. Methods The differentiation of bone marrow-derived dendritic cells (BMDC) was induced in vitro , and the effect of RHS2 on the maturation of DCs was evaluated. The effects of RHS2 on T cell activation and cytotoxic T lymphocytes’ (CTLs) activity were analyzed by flow cytometry. Antibody subtypes after immunization of mice with RHS2 and OVA were determined. Results RHS2 can inhibit the differentiation of bone marrow-derived cells into DCs and promote their differentiation into macrophages. RHS2 can inhibit the maturation of DCs and the expression of CD80, CD86 and MHCII. The number of CD3 + CD4 + and CD3 + CD8 + T cells secreting IFN-γ, IL-2 and TNF-α was decreased, and the number of CD3 + CD4 + T cells secreting IL-4 was increased, indicating that RHS2 can inhibit the activation of CD4 T cells and CD8 T cells, leading to inhibition of Th1 immune response. RHS2 inhibits the elimination of target cells by cytotoxic T lymphocytes. After immunization of mice with RHS2 and OVA, serum IgG2b was significantly reduced and IgM was increased. Conclusions The results show that RHS2 has an inhibitory effect on the host immune response. Ticks have evolved various ways to circumvent adaptive immunity. Their serpin inhibits BMDC differentiation to reduce immune responses.

A Comprehensive Phylogenetic Analysis of the Serpin Superfamily

“…2009 ; Chmelar et al. 2011 ; Xu et al. 2019 ) or prolong feeding by disrupting hemostatic proteolytic cascades ( Chmelar et al.…”

Naturally Acquired Resistance to Ixodes scapularis Elicits Partial Immunity against Other Tick Vectors in a Laboratory Host

“…One likely reason for this is that ticks are able to modulate host immune responses. 6,50,51 A recent study by Xu et al 52 showed that a tick serine protease inhibitor suppressed adaptive immune components, including IgG2, and it is conceivable that in guinea pigs, low levels of humoral immunity, in concert with cellular immunity, may be sufficient to induce a cutaneous hypersensitivity response. Passive transfer experiments comparing tick rejection induced by either immune serum or peritoneal exudate cells/lymph node cells have shown that cellular immunity has a greater effect than humoral immunity, although the differences are inconsistent among tick species and, to our knowledge, have not been reported for I. scapularis.…”

Tick Salivary Compounds for Targeted Immunomodulatory Therapy

“…Recombinant HL-p36 and RH36 also directly inhibited the proliferation of several mitogen-stimulated cells in vivo and the expression of several cytokines such as IL-2, IL-12, and TNF-α (141,142). In addition to its effect on DCs, RHS2 can prevent the activation of CD4 + and CD8 + T cells, leading to inhibition of the Th1 immune response (132). Two salivary cystatins from I. scapularis, Sialostatin L and Sialostatin L2, have shown promising anti-inflammatory and immunosuppressive activity in vitro and in vivo (141,142).…”

“…PGE 2 has been described as the major DC inhibitor (Figure 3) in both I. scapularis (130) and Amblyomma sculptum saliva (131). RHS2 from Rhipicephalus haemaphysaloides can inhibit the differentiation of BMDCs into DCs in vitro and promote their differentiation into macrophages (132). RHS2 also inhibits the expression of CD80, CD86, and the major histocompatibility complex class II (MHCII), thereby preventing DC maturation.…”