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Purpose Antimicrobial proteins (AMPs) in saliva including secretory immunoglobulin A (SIgA), lactoferrin (SLac) and lysozyme (SLys) are important in host defence against oral and respiratory infections. This study investigated the effects of hydration status on saliva AMP responses to endurance exercise. Methods Using a randomized design, 10 healthy male participants (age 23 ± 4 years, V ˙ O 2 max 56.8 ± 6.5 ml/kg/min) completed 2 h cycling at 60 % V ˙ O 2 max in states of euhydration (EH) or dehydration (DH) induced by 24 h fluid restriction. Unstimulated saliva samples were collected before, during, immediately post-exercise and each hour for 3 h recovery. Results Fluid restriction resulted in a 1.5 ± 0.5 % loss of body mass from baseline and a 4.3 ± 0.7 % loss immediately post-exercise. Pre-exercise urine osmolality was higher in DH than EH and overall, saliva flow rate was reduced in DH compared with EH ( p  < 0.05). Baseline SIgA secretion rates were not different between conditions; however, exercise induced a significant increase in SIgA concentration in DH (161 ± 134 to 309 ± 271 mg/L) which remained elevated throughout 3 h recovery. SLac secretion rates increased from pre- to post-exercise in both conditions which remained elevated in DH only. Overall, SLac concentrations were higher in DH than EH. Pre-exercise SLys concentrations were lower in DH compared with EH (1.6 ± 2.0 vs. 5.5 ± 6.7 mg/L). Post-exercise SLys concentrations remained elevated in DH but returned to pre-exercise levels by 1 h post-exercise in EH. Conclusions Exercise in DH caused a reduction in saliva flow rate yet induced greater secretion rates of SLac and higher concentrations of SIgA and SLys. Thus, DH does not impair saliva AMP responses to endurance exercise.

Objective Although Th17 cells have been increasingly recognised as an important effector in various autoimmune diseases, their function in the pathogenesis of Sjögren's syndrome (SS) remains largely uncharacterised. This study aims to determine the role of Th17 cells in the development of experimental SS (ESS). Methods The ESS was induced in wildtype and IL-17A knockout (IL-17 KO) C57BL/6 mice immunised with salivary glands (SG) proteins. Phenotypic analysis of immune cells in the draining cervical lymph nodes (CLN) and SG was performed by flow cytometry and immunofluorescence microscopy. To determine the role of Th17 cells in ESS, immunised IL-17 KO mice were adoptively transferred with in vitro-generated Th17 cells and monitored for SS development. The salivary flow rate was measured, whereas inflammatory infiltration and tissue destruction in SG were assessed by histopathology. Results SG protein-immunised mice developed overt SS symptoms with increased Th17 cells detected in CLN and within lymphocytic foci in inflamed SG. Notably, immunised IL-17 KO mice were completely resistant for SS induction, showing no evidence of disease symptoms and histopathological changes in SG. Adoptive transfer of Th17 cells rapidly induced the onset of ESS in immunised IL-17 KO mice with markedly reduced saliva secretion, elevated autoantibody production and pronounced inflammation and tissue damage in SG. Conclusions Our findings have defined a critical role of Th17 cells in the pathogenesis of ESS. Further studies may validate Th17 cell as a potential target for treating SS.

Leishmaniases are parasitic diseases present worldwide that are transmitted to the vertebrate host by the bite of an infected sand fly during a blood feeding. Phlebotomine sand flies inoculate into the mammalian host Leishmania parasites embedded in promastigote secretory gel (PSG) with saliva, which is composed of a diverse group of molecules with pharmacological and immunomodulatory properties. In this review, we focus on 3 main aspects of sand fly salivary molecules: (1) structure and composition of salivary glands, including the properties of salivary molecules related to hemostasis and blood feeding, (2) immunomodulatory properties of salivary molecules and the diverse impacts of these molecules on leishmaniasis, ranging from disease exacerbation to vaccine development, and (3) use of salivary molecules for field applications, including monitoring host exposure to sand flies and the risk of Leishmania transmission. Studies showed interesting differences between salivary proteins of Phlebotomus and Lutzomyia species, however, no data were ever published on salivary proteins of Sergentomyia species. In the last 15 years, numerous studies have characterized sand fly salivary proteins and, in parallel, have addressed the impact of such molecules on the biology of the host-sand fly-parasite interaction. The results obtained shall pave the way for the development of field-application tools that could contribute to the management of leishmaniasis in endemic areas.

Guinea pigs exposed to multiple infestations with Ixodes scapularis ticks develop acquired resistance to ticks, which is also known as tick immunity. The I. scapularis salivary components that contribute to tick immunity are likely multifactorial. An anticoagulant that inhibits factor Xa, named Salp14, is present in tick saliva and is associated with partial tick immunity. A tick bite naturally releases tick saliva proteins into the vertebrate host for several days, which suggests that the mode of antigen delivery may influence the genesis of tick immunity. We therefore utilized Salp14 as a model antigen to examine tick immunity using mRNA lipid nanoparticles (LNPs), plasmid DNA, or recombinant protein platforms. salp14 containing mRNA-LNPs vaccination elicited erythema at the tick bite site after tick challenge that occurred earlier, and that was more pronounced, compared with DNA or protein immunizations. Humoral and cellular responses associated with tick immunity were directed towards a 25 amino acid region of Salp14 at the carboxy terminus of the protein, as determined by antibody responses and skin-testing assays. This study demonstrates that the model of antigen delivery, also known as the vaccine platform, can influence the genesis of tick immunity in guinea pigs. mRNA-LNPs may be useful in helping to elicit erythema at the tick bite site, one of the most important early hallmarks of acquired tick resistance. mRNA-LNPs containing tick genes is a useful platform for the development of vaccines that can potentially prevent selected tick-borne diseases.

Repeated exposure of animals to Ixodes scapularis ticks can result in acquired tick resistance (ATR). The first manifestation of ATR is erythema at the tick bite site, however, the specific peptide targets and mechanisms associated with this early aspect of ATR are not understood. In this study, we immunized guinea pigs with a lipid nanoparticle containing the mRNA encoding 25 amino acids in the carboxyl terminus of Salp14 (Salp14-C mRNA-LNP), an I. scapularis salivary protein. The animals produced high titers of IgG directed at the carboxyl terminus of Salp14. Guinea pigs immunized with Salp14-C mRNA-LNP and then exposed to I. scapularis, developed erythema at the tick bite site. Transcriptomics of the skin of guinea pigs at the I. scapularis bite sites elucidated selected pathways, including histamine activation, that are associated with the development of erythema. The study demonstrates that an mRNA vaccine encoding a small peptide can induce the initial phase of ATR in guinea pigs.

Global warming is expanding mosquito habitats and increasing mosquito-borne diseases. In tropical and sub-tropical regions, chikungunya virus (CHIKV) transmitted by Aedes mosquitoes has become a major concern due to the debilitating chronic joint disease it causes. Mosquito saliva contains bioactive factors that enhance viral infection, with sialokinin identified as a key contributor to vascular leakage and viral spread in mice. Here, we demonstrate that sialokinin binds to neurokinin receptors and restricts the activation of human myeloid cells. Mechanistically, sialokinin facilitates early viral dissemination, as evidenced by increased viral load in the contralateral footpad at 1 day post-infection, and significantly reduces circulating CD169+ monocytes while suppressing IFN-γ-producing T-cell-driven inflammation, as reflected by reduced joint footpad swelling in female CHIKV-infected mice. Clinically, patients with severe CHIKV disease exhibited higher levels of IgG antibodies against sialokinin, which correlated with higher viral loads and systemic inflammatory markers. Our findings highlight the multifaceted role of sialokinin in facilitating early viral dissemination and modulating host immunity during CHIKV infection. Given the growing threat of mosquito-borne diseases in a warming, disease-burdened world, targeting mosquito salivary factors like sialokinin could offer a novel therapeutic strategy to mitigate viral-induced inflammation and improve clinical outcomes. The role of mosquito saliva proteins in viral infection remains incompletely understood. Here, the authors show that sialokinin facilitates viral dissemination while suppressing immune response and inflammation in chikungunya virus-infected mice.

The alpha-Gal syndrome (AGS) evolved as a catastrophic selection associated with anti-α-Gal IgM/IgG protective response against pathogen infection and tick-borne food allergy caused by IgE-type antibodies against this glycan present in glycoproteins and glycolipids from mammalian meat and derived products. The immune response to α-Gal is modulated by tick salivary proteins with and without α-Gal modifications in combination with tick saliva non-protein fraction. Herein, we characterized the role of tick salivary proteins, metalloprotease and allergen-like p23 in AGS and protection against tuberculosis in the AGS zebrafish animal model. Metalloprotease and p23 are involved in allergic reactions after mammalian meat consumption through upregulation of pro-inflammatory protein-coding genes prkdc , tlr2 , tnfα and il1b . Challenge with Mycobacterium marinum activated Th1-mediated immune protective response with reduced pathogen infection, ameliorating Th2-associated allergic reactions associated with AGS. These results highlight molecular mechanisms modulated by tick proteins in response to α-Gal and provide insights to reduce AGS impact on human health.

Tick salivary proteins are crucial for efficient and successful tick feeding. Most of them are still uncharacterized, especially those involved in the formation of tick cement. Tick salivary protein PA107 is a putative cement protein, which is transcribed in salivary glands during the initial phase of tick feeding. It is a tick-unique protein, with homologs described in several tick genera. In this study, a detailed in silico analysis of its primary and tertiary structure was performed, along with the immunogenicity assessment for the PA107 protein from Ixodes ricinus species. The screening of the primary structure placed it to the glycine-rich protein family, revealing in parallel an overlapping 15mer at the C-terminus and borderline homology to non-tick proteins with antimicrobial activity. The analysis of tertiary structure revealed a high degree of intrinsic disorder for monomeric PA107, in contrast to highly ordered structures for different oligomeric states that might correlate with the putative role in the tick cement formation process. Regarding in silico PA107 immunogenicity inference, obtained results were inconclusive, which aligns with the in vitro findings showing definitely the lack of humoral response induction in experimentally infested rats and persons bitten by the I. ricinus ticks. The results represent new pieces of a huge puzzle depicting a complex tick-host relationship, but also identify PA107 as a possible compound of novel formulations to be used in biomedicine as bioadhesives, and as a target for new anti-tick strategies, by interfering with the cement cone formation and stability, i.e. tick attachment and feeding.

Aedes aegypti mosquitoes transmit several arboviruses of public health importance. Among these is dengue virus (DENV), a flavivirus whose global infection rates continue to rise each year. With limited options available for preventing or treating DENV infections, mosquito control remains the most widely implemented strategy to combat DENV transmission. Due to the global distribution of DENV, which infects an estimated 400 million people per year, vector suppression practices vary drastically by country and/or region and even small differences in microenvironment can significantly impact vector abundance. There remains a significant need to better understand vector exposure rates at an individual level to disentangle vector exposure and arboviral infection rates. To this end, we have optimized a serologic assay to assess the abundance of antibodies directed against the mosquito salivary proteins AeD7L1 + 2 as a surrogate metric of vector exposure. Utilizing this assay, we found that anti-AeD7L1 + 2 IgG levels were unable to identify low levels of Aedes exposure in individuals with limited prior Aedes exposure, indicating they are unreliable markers of an individual’s recent exposure to low levels of these vectors. However, antibody levels against AeD7L1 + 2 were robust in plasma samples from individuals living in Aedes endemic regions. These antibody levels reflected seasonal changes in Aedes abundance and exposure, indicating their potential for use as an aggregate marker of vector exposure. Additionally, we found that there were negative associations with anti-AeD7L1 + 2 IgG levels and age in our cohort. Interestingly, we also found that lower titers of anti-AeD7L1 + 2 IgG correlated with higher infection burden in households. This finding has implications for the potential interaction between AeD7L1 + 2 proteins or anti-AeD7L1 + 2 antibodies and DENV during infection events that will require further study.

Phlebotomus argentipes is the established vector of leishmaniasis in the Indian sub-continent. Antibodies to sand fly salivary antigens are biomarkers for vector-host exposure in leishmaniasis-endemic regions. Ph. argentipes transmits Leishmania donovani in Sri Lanka, primarily causing cutaneous leishmaniasis (CL). Our study compared the performance of salivary gland homogenate (SGH) from a lab-reared local strain of Ph. argentipes females to a composite recombinant salivary biomarker (rPagSP02 + rPagSP06) in a CL-endemic population. Sera from 546 healthy individuals, 30 CL patients, and 15 non-endemic individuals were collected. Western blot analysis of Ph. argentipes SGH identified immunogenic bands between 15 kDa and 67 kDa, with bands of predicted molecular weight ∼of 15 kDa (SP02) and ∼28–30 kDa (SP06) as the major antibody targets. Indirect ELISAs using SGH or rPagSP02 + rPagSP06 antigens showed high sensitivity (96.7%) and specificity (100%), detecting comparable seropositivity in endemic populations. rPagSP02 + rPagSP06 exhibited enhanced discriminatory ability, supported by a strong positive correlation ( r  = 0.869) with SGH. Our findings indicate that the composite rPagSP02 + rPagSP06 salivary biomarker effectively identifies Ph. argentipes exposure in individuals living in Sri Lanka, showing promising potential for use in surveillance. These findings should be further validated to confirm the epidemiological applications in leishmaniasis-endemic regions.