{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T13:14:40Z","timestamp":1783689280702,"version":"3.55.0"},"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2021,6,3]],"date-time":"2021-06-03T00:00:00Z","timestamp":1622678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"Armed Forces Health Surveillance Division, Global Emerging Infections Surveillance (GEIS) Branch","award":["PRoMIS ID P0024_17_HS"],"award-info":[{"award-number":["PRoMIS ID P0024_17_HS"]}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Background<\/jats:title><jats:p>Sand fly saliva exposure plays an important role in immunity against leishmaniasis where it has mostly been associated with protection.<jats:italic>Phlebotomus (Ph<\/jats:italic>.<jats:italic>) alexandri<\/jats:italic>transmits<jats:italic>Leishmania (L<\/jats:italic>.<jats:italic>) infantum<\/jats:italic>, the causative agent of visceral leishmaniasis (VL), in Iraq. Our group recently demonstrated that 20% of Operation Iraqi Freedom (OIF) deployers had asymptomatic VL (AVL) indicative of prior infection by the parasite<jats:italic>L<\/jats:italic>.<jats:italic>infantum<\/jats:italic>. Little is known about<jats:italic>Ph<\/jats:italic>.<jats:italic>alexandri<\/jats:italic>saliva, and the human immune response to it has never been investigated. Here, we characterize the humoral and cellular immune response to vector saliva in OIF deployers naturally exposed to bites of<jats:italic>Ph<\/jats:italic>.<jats:italic>alexandri<\/jats:italic>and characterize their immunological profiles in association to AVL.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Methodology\/Principal findings<\/jats:title><jats:p>The humoral response to<jats:italic>Ph<\/jats:italic>.<jats:italic>alexandri<\/jats:italic>salivary gland homogenate (SGH) showed that 64% of 200 OIF deployers developed an antibody response. To assess the cellular immune response to saliva, we selected a subcohort of subjects based on their post-travel (median 4 months; range 1\u201322 months) antibody response (SGH Antibody [Ab] positive or negative) as well as their AVL status; ten never-traveled controls were also included. Banked peripheral blood mononuclear cells (PBMC), collected ~10 years after end of deployment, were stimulated with SGH for 96 hours. The levels of IFN- \u03b3, IL-6, IL-10, IL-13 and IL-17 were determined by ELISA. Our findings indicate that OIF deployers mounted a cellular response to SGH where the anti-SGH+ asymptomatic subjects developed the highest cytokine levels. Further, stimulation with SGH produced a mixture of pro-inflammatory and anti-inflammatory cytokines. Contrary to our hypothesis, we observed no correlation between the cellular immune response to<jats:italic>Ph<\/jats:italic>.<jats:italic>alexandri<\/jats:italic>SGH and prevention from asymptomatic infection with<jats:italic>L<\/jats:italic>.<jats:italic>infantum<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Conclusions\/Significance<\/jats:title><jats:p>As we found, although all infected deployers demonstrated persistent disease control years after deployment, this did not correlate with anti-saliva systemic cellular response. More exposure to this vector may facilitate transmission of the<jats:italic>L<\/jats:italic>.<jats:italic>infantum<\/jats:italic>parasite. Since exposure to saliva of<jats:italic>Ph<\/jats:italic>.<jats:italic>alexandri<\/jats:italic>may alter the human immune response to bites of this vector, this parameter should be taken into consideration when considering the VL risk.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pntd.0009378","type":"journal-article","created":{"date-parts":[[2021,6,3]],"date-time":"2021-06-03T17:29:34Z","timestamp":1622741374000},"page":"e0009378","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["The human immune response to saliva of Phlebotomus alexandri, the vector of visceral leishmaniasis in Iraq, and its relationship to sand fly exposure and infection"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6811-6534","authenticated-orcid":true,"given":"Ines","family":"Lakhal-Naouar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1985-5717","authenticated-orcid":true,"given":"Rami","family":"Mukbel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7601-5469","authenticated-orcid":true,"given":"Robert F.","family":"DeFraites","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3862-4495","authenticated-orcid":true,"given":"Rupal M.","family":"Mody","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina N.","family":"Massoud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9531-1917","authenticated-orcid":true,"given":"Dutchabong","family":"Shaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edgie M.","family":"Co","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0373-737X","authenticated-orcid":true,"given":"Jeffrey E.","family":"Sherwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4304-636X","authenticated-orcid":true,"given":"Shaden","family":"Kamhawi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi E.","family":"Aronson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,6,3]]},"reference":[{"issue":"10","key":"pntd.0009378.ref001","doi-asserted-by":"crossref","first-page":"e3208","DOI":"10.1371\/journal.pntd.0003208","article-title":"Leishmaniasis in the middle East: incidence and epidemiology","volume":"8","author":"N Salam","year":"2014","journal-title":"PLoS Negl Trop Dis"},{"issue":"1","key":"pntd.0009378.ref002","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1179\/136485906X78454","article-title":"Phlebotomus (Paraphlebotomus) alexandri: a probable vector of Leishmania infantum in Iran","volume":"100","author":"K Azizi","year":"2006","journal-title":"Ann Trop Med Parasitol"},{"issue":"2","key":"pntd.0009378.ref003","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1111\/j.1948-7134.2013.12059.x","article-title":"Sand fly surveillance and control on Camp Ramadi, Iraq, as part of a leishmaniasis control program","volume":"38","author":"CA Stoops","year":"2013","journal-title":"J Vector Ecol"},{"issue":"3","key":"pntd.0009378.ref004","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1603\/033.046.0333","article-title":"Impact of phlebotomine sand flies on U.S. military operations at Tallil Air Base, Iraq: 4. 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