Leishmania rely heavily on glycans to complete their digenetic life cycle in both mammalian and phlebotomine sand fly hosts. Leishmania promastigotes secrete a proteophosphoglycan-rich gel (Promastigote Secretory Gel, PSG) that is regurgitated during transmission and can exacerbate infection in the skin. Here we explored the role of PSG from natural Leishmania-sand fly vector combinations by obtaining PSG from Leishmania (L.) major-infected Phlebotomus (P.) papatasi and P. duboscqi and L. tropica-infected P. arabicus. We found that, in addition to the vector's saliva, the PSG from L. major and L. tropica potently exacerbated cutaneous infection in BALB/c mice, improved the probability of developing a patent cutaneous lesion, parasite growth and the evolution of the lesion. Of note, the presence of PSG in the inoculum more than halved the prepatent period of cutaneous L. tropica infection from an average of 32 weeks to 13 weeks. In addition, L. major and L. tropica PSG extracted from the permissive experimental vector, Lutzomyia (Lu.) longipalpis, also exacerbated infections in mice. These results reinforce and extend the hypothesis that PSG is an important and evolutionarily conserved component of Leishmania infection that can be used to facilitate experimental infection for drug and vaccine screening.

Department of Parasitology Faculty of Science Charles University Prague Prague Czech Republic

Faculty of Infectious Tropical Diseases Department of Disease Control London School of Hygiene and Tropical Medicine London UK

Faculty of Infectious Tropical Diseases Department of Immunology and Infection London School of Hygiene and Tropical Medicine London UK

Faculty of Medicine Division of Infectious Diseases Department of Medicine Section of Immunology at St Mary's Imperial College London London UK

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Anderson CF, Lira R, Kamhawi S, Belkaid Y, Wynn TA and Sacks D (2008) IL-10 and TGF-beta control the establishment of persistent and transmissible infections produced by PubMed

Atayde VD, Aslan H, Townsend S, Hassani K, Kamhawi S and Olivier M (2015) Exosome secretion by the parasitic protozoan PubMed PMC

Badirzadeh A, Taheri T, Taslimi Y, Abdossamadi Z, Heidari-Kharaji M, Gholami E, Sedaghat B, Niyyat M and Rafati S (2017) Arginase activity in pathogenic and non-pathogenic species of PubMed PMC

Bates PA (1997) Transmission of PubMed PMC

Belkaid Y, Kamhawi S, Modi G, Valenzuela J, Noben-Trauth N, Rowton E, Ribeiro J and Sacks DL (1998) Development of a natural model of cutaneous leishmaniasis: powerful effects of vector saliva and saliva pre-exposure on the long-term outcome of PubMed PMC

Dey R, Joshi AB, Oliveira F, Pereira L, Guimarães-Costa AB, Serafim TD, de Castro W, Coutinho-Abreu IV, Bhattacharya P, Townsend S, Aslan H, Perkins A, Karmakar S, Ismail N, Karetnick M, Meneses C, Duncan R, Nakhasi HL, Valenzuela JG and Kamhawi S (2018) Gut microbes egested during bites of infected sand flies augment severity of leishmaniasis PubMed PMC

Dvorak V, Shaw J and Volf P (2018) Parasite biology: the vectors In Bruschi F and Gradoni L (eds), The Leishmaniases Old Neglected Tropical Diseases. Switzerland: Springer International Publishing AG, pp. 31–77. ISBN 978-3-319-72385-3. Available at 10.1007/978-3-319-72386-0. DOI

Gebre-Michael T, Balkew M, Ali A, Ludovisi A and Gramiccia M (2004) The isolation of PubMed

Giraud E, Lestinova T, Derrick T, Martin O, Dillon RJ, Volf P, Műller I, Bates PA and Rogers ME (2018) PubMed PMC

Giraud E, Martin O, Yakob L and Rogers M (2019) Quantifying PubMed PMC

Green SJ, Meltzer MS, Hibbs JB and Nacy CA Jr (1990) Activated macrophages destroy intracellular PubMed

Ilg T (2000) Proteophosphoglycans of PubMed

Ilg T, Stierhof YD, Craik D, Simpson R, Handman E and Bacic A (1996) Purification and structural characterization of a filamentous, mucin-like proteophosphoglycan secreted by PubMed

Jacobson RL, Eisenberger CL, Svobodová M, Baneth G, Sztern J, Carvalho J, Nasereddin A, El Fari M, Shalom U, Volf P, Votypka J, Dedet JP, Pratlong F, Schonian G, Schnur LF, Jaffe CL and Warburg A (2003) Outbreak of cutaneous leishmaniasis in northern Israel. Journal of Infectious Diseases 188, 1065–1073. PubMed

Kamhawi S, Belkaid Y, Modi G, Rowton E and Sacks DL (2000) Protection against cutaneous leishmaniasis resulting from bites of uninfected sandflies. Science 290, 1351–1354. PubMed

Kimblin N, Peters N, Debrabant A, Secundino N, Egen J, Lawyer P, Fay MP, Kamhawi S and Sacks D (2008) Quantification of the infectious dose of PubMed PMC

Klaus S and Frankenburg S (1999) Cutaneous leishmaniasis in the Middle East. Clinical Dermatology 17, 137–141. PubMed

Kobets T, Havelková H, Grekov I, Volkova V, Vojtíšková J, Slapničková M, Kurey I, Sohrabi Y, Svobodová M, Demant P and Lipoldová M (2012) Genetics of host response to PubMed PMC

Lira R, Méndez S, Carrera L, Jaffe C, Neva F and Sacks D (1998) PubMed

Maroli M, Feliciangeli MD, Bichaud L, Charrel RN and Gradoni L (2013) Phlebotomine sandflies and the spreading of leishmaniases and other diseases of public health concern. Medical and Veterinary Entomology 27, 123–147. PubMed

Montgomery J, Curtis J and Handman E (2002) Genetic and structural heterogeneity of proteophosphoglycans in PubMed

Mortazavi H, Sadeghipour P, Taslimi Y, Habibzadeh S, Zali F, Zahedifard F, Rahmati J, Kamyab K, Ghandi N, Zamanian A, Reza Tohidinik H, Muller I, Kropf P and Rafati S (2016) Comparing acute and chronic human cutaneous leishmaniasis caused by PubMed

Myskova J, Svobodova M, Beverley SM and Volf P (2007) A lipophosphoglycan-independent development of PubMed PMC

Noben-Trauth N, Kropf P and Müller I (1996) Susceptibility to PubMed

Rath M, Müller I, Kropf P, Closs EI and Munder M (2014) Metabolism PubMed PMC

Rogers ME (2012) The role of PubMed PMC

Rogers ME and Bates PA (2007) PubMed PMC

Rogers ME, Chance ML and Bates PA (2002) The role of promastigote secretory gel in the origin and transmission of the infective stage of PubMed

Rogers ME, Ilg T, Nikolaev AV, Ferguson MA and Bates PA (2004) Transmission of cutaneous leishmaniasis by sand flies is enhanced by regurgitation of fPPG. Nature 430, 463–467. PubMed PMC

Rogers M, Kropf P, Choi BS, Dillon R, Podinovskaia M, Bates P and Müller I (2009) Proteophosphoglycans regurgitated by PubMed PMC

Rogers ME, Corware K, Müller I and Bates PA (2010) PubMed

Serafim TD, Dey R, Nakhasi HL, Valunzuela JG and Kamhawi S (2017) Unique features of vector-transmitted leishmaniasis and their relevance to disease transmission and control In Wikel SK, Aksoy S and Dimopoulos G (eds), Arthropod Vector: Controller of Disease Transmission, Volume 2. Vector Saliva-Host-Pathogen Interactions. United States of America: Academic Press, pp. 91–114.

Shortt HE and Swaminath CS (1928) The method of feeding of

Stierhof YD, Bates PA, Jacobson RL, Rogers ME, Schlein Y, Handman E and Ilg T (1999) Filamentous proteophosphoglycan secreted by PubMed

Svobodová M, Votýpka J, Nicolas L and Volf P (2003) PubMed

Svobodová M, Volf P and Votýpka J (2006a) Experimental transmission of PubMed

Svobodova M, Votypka J, Peckova J, Dvorak V, Nasereddin A, Baneth G, Sztern J, Kravchenko V, Orr A, Meir D, Schnur LF, Volf P and Warburg A (2006b) Distinct transmission cycles of PubMed PMC

Titus RG and Ribeiro JM (1988) Salivary gland lysates from the sand fly PubMed

Volf P and Myskova J (2007) Sand flies and PubMed PMC

Volfova V, Hostomska J, Cerny M, Votypka J and Volf P (2008) Hyaluronidase of bloodsucking insects and its enhancing effect on PubMed PMC

Characterization of a new Leishmania major strain for use in a controlled human infection model