Abstract
Leishmania, being an intelligent protozoan parasite, modulates the defensive arsenals of the host to create a favorable niche for their survival. When the intracellular parasite is encountered by the host, multimeric complexes of inflammasomes get assembled and activated, thereby leading to genesis of inflammatory response. In order to subvert host defensive strategies, Leishmania utilizes their cyclic adenosine monophosphate (cAMP) and cAMP-induced response to neutralize macrophage oxidative damage. In this chapter, we summarize our current understanding of the mechanisms of inflammasome activation in macrophages and cAMP homeostasis of the parasite, leading to parasite viability within the macrophages and establishment of infection. Furthermore, we took into account, recent progresses in translating these research areas into therapeutic strategies, aimed at combating macrophage associated diseases.
Keywords
- inflammasome
- NLRP3
- cAMP homeostasis
- phagosome
- Leishmania
- macrophage
1. Introduction
Leishmaniases involve a broad spectrum of neglected tropical diseases that are caused by kinetoplastid parasites belonging to the genus
Another major modulator of cytological events in
2. Epidemiology of leishmaniasis
Visceral leishmaniasis, also known as kala-azar, is a deadly disease and in over 95% of instances it is found to be direful when left untreated. Approximately 50,000–90,000 new incidents of visceral leishmaniasis seem to occur globally each year in countries like Bangladesh, Brazil, China, Ethiopia, India, Kenya, Nepal, Somalia, South Sudan and Sudan. Cutaneous and mucocutaneous leishmaniasis occur in South American countries, Mediterranean river basin, the Central Asia and Middle East. Over 90% of mucocutaneous leishmaniasis cases occur in Bolivia, Brazil, Ethiopia and Peru [9]. The diseases collectively affect more than 1 million people every year, visceral leishmaniasis being the main reason for the death of a vast population of about 20,000–40,000 people annually [10]. Apart from humans, the primary host of the diseases, dogs, rodents, other mammals and few reptilian species act as the reservoir hosts of leishmaniases [11].
3. Parasite infection and activation of parasite-dependent host biology modulation
3.1 Initial events of parasite infection and macrophage activation
The disease manifestation of VL strictly relies on host immunocompetency ranging from asymptomatic forms to severe disease conditions, which if left untreated, can be fatal. Clinical conditions such as HIV infection or immunosuppression due to any drug treatment leading to immunodepression in host weaken the efficiency of the host immune system to deal with the infection and permit recurrence of the disease. The contrast in host–parasite interactions between cutaneous and visceral leishmaniasis is quite noteworthy, suggesting the role of infecting species of
3.1.1 Recognition and uptake
During the parasite’s transfer from its vector to the vertebrate host, neutrophils and macrophages are quickly recruited to the sand fly bite site [17]. The parasites secret proteophosphoglycans inside sandfly midgut which acts as a potent stimulator for recruiting macrophages at the site of infection as found in both
After the event of parasite recognition by macrophage cell surface, promastigotes are internalized by cholesterol-rich caveolae for both
3.1.2 Phagosome maturation and parasite differentiation
Following phagocytosis of the promastigotes by the macrophages and their internalization into the phagosome, the parasites fuse with lysosomes and adapt to the hostile environment where they must survive for disease manifestations. Despite the fact that this is one of the most difficult habitats for most infectious pathogens,
Differentiation from promastigote to amastigote is triggered by an increase in temperature from 22–37°C and a decrease in pH from 7.2 to 5.5 in mammalian phagolysosomes. Furthermore, iron uptake followed by hydrogen peroxide generation has been found to be a significant trigger for parasitic differentiation in
3.1.3 Macrophage activation: host: parasite interaction
Macrophages, apart from acting as a phagocytic cell, respond to and regulate different signaling molecules [37]. Circulating monocytes are the precursors of tissue macrophages that secrete various antimicrobial and immunoregulatory molecules capable of inactivating pathogens through ROS and NO generation [38, 39, 40]. Monocyte–macrophage lineage show notable plasticity and can modify their physiology according to the environmental stimuli giving rise to diversified cell population with different functions [41, 42]. The state of activation of macrophages can be changed in response to different cytokines, growth factors and microbial molecules. When stimulated by TNF-α or IFN-γ or lipopolysaccharide, macrophages undergo classical activation that is characterized by surface marker CD80 expression [43, 44]. On the other hand, macrophages undergoing alternative activation is induced by IL-4 and IL-13 by the activation of a common receptor, IL-4R [45]. Production of high levels IL-13, CCL14, CCL17, CCL18, CCL22, IL-10, TGF-β, urea, and ornithine which is an essential substrate for both polyamine and collagen synthesis, are observed in alternatively activated macrophages [44, 46, 47]. One of the mechanisms for the establishment of intra-macrophage parasite infection is the inhibition of host defense mechanism which is achieved by inhibiting inflammatory cytokine secretion and apoptosis. One such target of
3.2 Inflammasome activation by Leishmania : mastering the macrophage environment exploiting macrophage biology
Upon detection of pathogenic organisms, the cytoplasm of the cells of innate immunity assembles multiprotein complexes called inflammasomes that cause an inflammatory programmed cell death called pyroptosis. The nucleotide-binding domain leucine-rich repeat protein (NLR) family is the widely studied inflammasome that is activated by cell membrane damage-inducing pathogens and molecules (Figure 1) [49]. Caspase-1 activation is promoted upon NLRP3 activation and oligomerization which leads to ASC polymerization exposing the CARD domains of the ASC, leading to recruitment of Caspase-1 through CARD/CARD interaction. The NLRP3 inflammasome undergoes both canonical and non-canonical activation. Initially, TLR (toll-like receptors) or TNFRs are stimulated by microbial components or TNF-α leading to numerous inflammatory gene transcription, Nlrp3, Casp11 and Il1b for instance. But inspite of the presence of a first signal, a second signal is required for canonical NLRP3 activation that occurs via pore formation by the microbial toxins, and subsequent rupture of the host cell membrane, resulting in K+ efflux and decrease in K+ concentration the cytoplasm [50]. Apart from potassium efflux, lysosomal cathepsin and ROS production is also essential for canonical activation of NLRP3. In contrast, non-canonical activation of NLRP3 inflammasomes is promoted by Caspase-11 which is activated by bacterial LPS. Different species of
3.3 The NLRP3 inflammasome and its activation during Leishmania sp. infection
Initial stage of macrophage infection by
4. Leishmania evades host defense
4.1 Curbing inflammation
To counter host defenses,
4.2 Interfering with host cell signaling
4.3 Avoiding oxidative damage
The reactions of
4.4 Countering antigen presentation
Antigen cross-presentation is a significant aspect in pathogen immunity. It entails presenting phagocytosed cargo-derived foreign proteins on class I MHC for cytotoxic CD8+ T cells recognition and a systemic immune response coordination. The macrophage, as a specialized antigen presenting cell (APC), contributes in the cross-presentation of proteins generated from
4.5 Inducing autophagy
4.6 Exploiting macrophage environment to activate its antioxidant defense mechanism through cyclic nucleotide signaling pathway
Following phagocytosis by macrophages in the early stages of infection, the parasites are subjected to severe oxidative stress as a result of a respiratory burst offered by the macrophages releasing ROS and RNS [78, 79]. Superoxide dismutase, peroxidoxin, and trypanothione reductase are three
5. Role of cAMP in survival and infectivity of the parasites
In eukaryotes, cAMP, a second messenger which is formed from ATP by the membrane- bound enzyme, receptor adenylate cyclases (RAC), is a key component that controls a wide range of cellular activities such as cytoskeletal modeling, cell proliferation, virulence, cellular differentiation, and death [85]. There have been reports of various isoforms of both membrane-bound receptor adenylate cyclases and soluble adenylate cyclases in
Despite the fact that cAMP-dependent protein kinase (PKA) exists and functions in eukaryotes, the role of PKA in cAMP signaling in this specific parasite is still ambiguous. PKA, being the first downstream effector of cAMP in the RAC pathway, facilitate γ-P transfer to particular ser/thr residue from ATP [95]. Upon exposure of
6. Conclusion
Being an intracellular parasite,
Acknowledgments
We would like to thank Personal Research Grant (PRG), University of Kalyani, DST-PURSE, University of Kalyani and INSA Senior Scientist Fellowship for contingent costs associated with the drafting of this chapter.
References
- 1.
Rogers ME. The role of Leishmania Proteophosphoglycans in sand Fly transmission and infection of the mammalian host. Frontiers in Microbiology. 2012; 3 :223 - 2.
Heyde S, Philipsen L, Formaglio P, Fu Y, Baars I, Höbbel G, et al. CD11c-expressing Ly6C+CCR2+ monocytes constitute a reservoir for efficient Leishmania proliferation and cell-to-cell transmission. PLoS Pathogens. 2018; 14 (10):e1007374 - 3.
Kelley N, Jeltema D, Duan Y, He Y. The NLRP3 Inflammasome: An overview of mechanisms of activation and regulation. International Journal of Molecular Sciences. 2019; 20 (13):3328 - 4.
de Carvalho RVH, Zamboni DS. Inflammasome activation in response to intracellular protozoan parasites. Trends in Parasitology. 2020; 36 (5):459-472 - 5.
Lecoeur H, Prina E, Rosazza T, Kokou K, N’Diaye P, Aulner N, et al. Targeting macrophage histone H3 modification as a Leishmania strategy to dampen the NF-κB/NLRP3-mediated inflammatory response. Cell Reports. 2020; 30 (6):1870-1882.e4 - 6.
Biswas A, Bhattacharya A, Das PK. Role of cAMP Signaling in the survival and infectivity of the protozoan parasite, Leishmania donovani. Molecular Biology International. 2011; 2011 :e782971 - 7.
Saha A, Bhattacharjee A, Vij A, Das PK, Bhattacharya A, Biswas A. Evaluation of modulators of cAMP-response in terms of their impact on cell cycle and mitochondrial activity of Leishmania donovani. Frontiers in Pharmacology. 2020; 11 :782 - 8.
Bhattacharya A, Biswas A, Das PK. Role of intracellular cAMP in differentiation-coupled induction of resistance against oxidative damage in Leishmania donovani. Free Radical Biology & Medicine. 2008; 44 (5):779-794 - 9.
Casalle N, de Barros Pinto Grifoni L, Bosco Mendes AC, Delort S, Massucato EMS. Mucocutaneous Leishmaniasis with rare manifestation in the nasal mucosa and cartilage bone septal. Case Reports in Infectious Diseases. 2020; 2020 :8876020 - 10.
Alvar J, Vélez ID, Bern C, Herrero M, Desjeux P, Cano J, et al. Leishmaniasis worldwide and global estimates of its incidence. PLoS One. 2012; 7 (5):e35671 - 11.
Ready PD. Epidemiology of visceral leishmaniasis. Clinical Epidemiology. 2014; 6 :147-154 - 12.
McMahon-Pratt D, Alexander J. Does the Leishmania major paradigm of pathogenesis and protection hold for New World cutaneous leishmaniases or the visceral disease? Immunological Reviews. 2004; 201 :206-224 - 13.
Domínguez M, Moreno I, Aizpurua C, Toraño A. Early mechanisms of Leishmania infection in human blood. Microbes and Infection. 2003; 5 (6):507-513 - 14.
Maurer M, Dondji B, von Stebut E. What determines the success or failure of intracellular cutaneous parasites? Lessons learned from leishmaniasis. Medical Microbiology and Immunology. 2009; 198 (3):137-146 - 15.
Scharton TM, Scott P. Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. The Journal of Experimental Medicine. 1993; 178 (2):567-577 - 16.
Sundar S, Reed SG, Sharma S, Mehrotra A, Murray HW. Circulating T helper 1 (Th1) cell- and Th2 cell-associated cytokines in Indian patients with visceral leishmaniasis. The American Journal of Tropical Medicine and Hygiene. 1997; 56 (5):522-525 - 17.
Peters NC, Egen JG, Secundino N, Debrabant A, Kimblin N, Kamhawi S, et al. In vivo imaging reveals an essential role for neutrophils in leishmaniasis transmitted by sand flies. Science. 2008; 321 (5891):970-974 - 18.
Rogers M, Kropf P, Choi B-S, Dillon R, Podinovskaia M, Bates P, et al. Proteophosophoglycans regurgitated by Leishmania-infected sand flies target the L-arginine metabolism of host macrophages to promote parasite survival. PLoS Pathogens. 2009; 5 (8):e1000555 - 19.
Rogers ME, Corware K, Müller I, Bates PA. Leishmania infantum proteophosphoglycans regurgitated by the bite of its natural sand fly vector, Lutzomyia longipalpis, promote parasite establishment in mouse skin and skin-distant tissues. Microbes and Infection. 2010; 12 (11):875-879 - 20.
Rotureau B, Morales MA, Bastin P, Späth GF. The flagellum-mitogen-activated protein kinase connection in Trypanosomatids: A key sensory role in parasite signalling and development? Cellular Microbiology. 2009; 11 (5):710-718 - 21.
Peters NC, Sacks DL. The impact of vector-mediated neutrophil recruitment on cutaneous leishmaniasis. Cellular Microbiology. 2009; 11 (9):1290-1296 - 22.
Mollinedo F, Janssen H, de la Iglesia-Vicente J, Villa-Pulgarin JA, Calafat J. Selective fusion of azurophilic granules with Leishmania-containing phagosomes in human neutrophils. The Journal of Biological Chemistry. 2010; 285 (45):34528-34536 - 23.
Ueno N, Wilson ME. Receptor-mediated phagocytosis of Leishmania: Implications for intracellular survival. Trends in Parasitology. 2012; 28 (8):335-344 - 24.
Rodríguez NE, Gaur Dixit U, Allen L-AH, Wilson ME. Stage-specific pathways of Leishmania infantum chagasi entry and phagosome maturation in macrophages. PLoS One. 2011; 6 (4):e19000 - 25.
Chattopadhyay A, Jafurulla M. Role of membrane cholesterol in leishmanial infection. Advances in Experimental Medicine and Biology. 2012; 749 :201-213 - 26.
Roy S, Kumar GA, Jafurulla M, Mandal C, Chattopadhyay A. Integrity of the actin cytoskeleton of host macrophages is essential for Leishmania donovani infection. Biochimica et Biophysica Acta. 2014; 1838 (8):2011-2018 - 27.
Majumder S, Dey R, Bhattacharjee S, Rub A, Gupta G, Bhattacharyya Majumdar S, et al. Leishmania-induced biphasic ceramide generation in macrophages is crucial for uptake and survival of the parasite. The Journal of Infectious Diseases. 2012; 205 (10):1607-1616 - 28.
Mukherjee M, Basu Ball W, Das PK. Leishmania donovani activates SREBP2 to modulate macrophage membrane cholesterol and mitochondrial oxidants for establishment of infection. The International Journal of Biochemistry & Cell Biology. 2014; 55 :196-208 - 29.
Vinet AF, Fukuda M, Turco SJ, Descoteaux A. The Leishmania donovani lipophosphoglycan excludes the vesicular proton-ATPase from phagosomes by impairing the recruitment of synaptotagmin V. PLoS Pathogens. 2009; 5 (10):e1000628 - 30.
Moradin N, Descoteaux A. Leishmania promastigotes: Building a safe niche within macrophages. Frontiers in Cellular and Infection Microbiology. 2012; 2 :121 - 31.
Forestier C-L, Machu C, Loussert C, Pescher P, Späth GF. Imaging host cell-Leishmania interaction dynamics implicates parasite motility, lysosome recruitment, and host cell wounding in the infection process. Cell Host & Microbe. 2011; 9 (4):319-330 - 32.
Mittra B, Cortez M, Haydock A, Ramasamy G, Myler PJ, Andrews NW. Iron uptake controls the generation of Leishmania infective forms through regulation of ROS levels. The Journal of Experimental Medicine. 2013; 210 (2):401-416 - 33.
Mittra B, Andrews NW. IRONy OF FATE: Role of iron-mediated ROS in Leishmania differentiation. Trends in Parasitology. 2013; 29 (10):489-496 - 34.
Podinovskaia M, Descoteaux A. Leishmania and the macrophage: A multifaceted interaction. Future Microbiology. 2015; 10 (1):111-129 - 35.
Vij A, Biswas A, Bhattacharya A, Das PK. A soluble phosphodiesterase in Leishmania donovani negatively regulates cAMP signaling by inhibiting protein kinase a through a two way process involving catalytic as well as non-catalytic sites. The International Journal of Biochemistry & Cell Biology. 2014; 57 :197-206 - 36.
Biswas A, Bhattacharya A, Vij A, Das PK. Role of leishmanial acidocalcisomal pyrophosphatase in the cAMP homeostasis in phagolysosome conditions required for intra-macrophage survival. The International Journal of Biochemistry & Cell Biology. 2017; 86 :1-13 - 37.
Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013; 496 (7446):445-455 - 38.
Nathan CF, Hibbs JB. Role of nitric oxide synthesis in macrophage antimicrobial activity. Current Opinion in Immunology. 1991; 3 (1):65-70 - 39.
Forman HJ, Torres M. Reactive oxygen species and cell signaling: Respiratory burst in macrophage signaling. American Journal of Respiratory and Critical Care Medicine. 2002; 166 (12 Pt 2):S4-S8 - 40.
Franken L, Schiwon M, Kurts C. Macrophages: Sentinels and regulators of the immune system. Cellular Microbiology. 2016; 18 (4):475-487 - 41.
Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nature Reviews. Immunology. 2005; 5 (12):953-964 - 42.
Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nature Reviews. Immunology. 2008; 8 (12):958-969 - 43.
Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. The Journal of Clinical Investigation. 2012; 122 (3):787-795 - 44.
Jaguin M, Houlbert N, Fardel O, Lecureur V. Polarization profiles of human M-CSF-generated macrophages and comparison of M1-markers in classically activated macrophages from GM-CSF and M-CSF origin. Cellular Immunology. 2013; 281 (1):51-61 - 45.
Gordon S, Martinez FO. Alternative activation of macrophages: Mechanism and functions. Immunity. 2010; 32 (5):593-604 - 46.
Mills CD. Macrophage arginine metabolism to ornithine/urea or nitric oxide/citrulline: A life or death issue. Critical Reviews in Immunology. 2001; 21 (5):399-425 - 47.
Tarique AA, Logan J, Thomas E, Holt PG, Sly PD, Fantino E. Phenotypic, functional, and plasticity features of classical and alternatively activated human macrophages. American Journal of Respiratory Cell and Molecular Biology. 2015; 53 (5):676-688 - 48.
Gupta P, Srivastav S, Saha S, Das PK, Ukil A. Leishmania donovani inhibits macrophage apoptosis and pro-inflammatory response through AKT-mediated regulation of β-catenin and FOXO-1. Cell Death and Differentiation. 2016; 23 (11):1815-1826 - 49.
Broz P, Dixit VM. Inflammasomes: Mechanism of assembly, regulation and signalling. Nature Reviews. Immunology. 2016; 16 (7):407-420 - 50.
Di A, Xiong S, Ye Z, Malireddi RKS, Kometani S, Zhong M, et al. The TWIK2 potassium Efflux Channel in macrophages mediates NLRP3 Inflammasome-induced inflammation. Immunity. 2018; 49 (1):56-65.e4 - 51.
Shio MT, Christian JG, Jung JY, Chang K-P, Olivier M. PKC/ROS-mediated NLRP3 Inflammasome activation is attenuated by Leishmania zinc-metalloprotease during infection. PLoS Neglected Tropical Diseases. 2015; 9 (6):e0003868 - 52.
Gupta AK, Ghosh K, Palit S, Barua J, Das PK, Ukil A. Leishmania donovani inhibits inflammasome-dependent macrophage activation by exploiting the negative regulatory proteins A20 and UCP2. The FASEB Journal. 2017; 31 (11):5087-5101 - 53.
Ball WB, Mukherjee M, Srivastav S, Das PK. Leishmania donovani activates uncoupling protein 2 transcription to suppress mitochondrial oxidative burst through differential modulation of SREBP2, Sp1 and USF1 transcription factors. The International Journal of Biochemistry & Cell Biology. 2014; 48 :66-76 - 54.
Saha G, Khamar BM, Singh OP, Sundar S, Dubey VK. Leishmania donovani evades caspase 1 dependent host defense mechanism during infection. International Journal of Biological Macromolecules. 2019; 126 :392-401 - 55.
Lima-Junior DS, Costa DL, Carregaro V, Cunha LD, Silva ALN, Mineo TWP, et al. Inflammasome-derived IL-1β production induces nitric oxide-mediated resistance to Leishmania. Nature Medicine. 2013; 19 (7):909-915 - 56.
Lefèvre L, Lugo-Villarino G, Meunier E, Valentin A, Olagnier D, Authier H, et al. The C-type lectin receptors dectin-1, MR, and SIGNR3 contribute both positively and negatively to the macrophage response to Leishmania infantum. Immunity. 2013; 38 (5):1038-1049 - 57.
Lima-Junior DS, Mineo TWP, Calich VLG, Zamboni DS. Dectin-1 activation during Leishmania amazonensis phagocytosis prompts Syk-dependent reactive oxygen species production to trigger Inflammasome assembly and restriction of parasite replication. Journal of Immunology. 2017; 199 (6):2055-2068 - 58.
de Carvalho RVH, Andrade WA, Lima-Junior DS, Dilucca M, de Oliveira CV, Wang K, et al. Leishmania Lipophosphoglycan triggers Caspase-11 and the non-canonical activation of the NLRP3 Inflammasome. Cell Reports. 2019; 26 (2):429-437.e5 - 59.
Farias Luz N, Balaji S, Okuda K, Barreto AS, Bertin J, Gough PJ, et al. RIPK1 and PGAM5 control Leishmania replication through distinct mechanisms. Journal of Immunology. 2016; 196 (12):5056-5063 - 60.
Santos DM, Carneiro MW, de Moura TR, Soto M, Luz NF, Prates DB, et al. PLGA nanoparticles loaded with KMP-11 stimulate innate immunity and induce the killing of Leishmania. Nanomedicine. 2013; 9 (7):985-995 - 61.
Miranda MM, Panis C, da Silva SS, Macri JA, Kawakami NY, Hayashida TH, et al. Kaurenoic acid possesses leishmanicidal activity by triggering a NLRP12/IL-1β/cNOS/NO pathway. Mediators of Inflammation. 2015; 2015 :392918 - 62.
Lapara NJ, Kelly BL. Suppression of LPS-induced inflammatory responses in macrophages infected with Leishmania. Journal of Inflammation. 2010; 7 (1):8 - 63.
Chan MM, Adapala N, Chen C. Peroxisome proliferator-activated receptor-γ-mediated polarization of macrophages in Leishmania infection. PPAR Research. 2012; 2012 :796235 - 64.
Gómez MA, Olivier M. Proteases and phosphatases during Leishmania-macrophage interaction: Paving the road for pathogenesis. Virulence. 2010; 1 (4):314-318 - 65.
Liu D, Uzonna JE. The early interaction of Leishmania with macrophages and dendritic cells and its influence on the host immune response. Frontiers in Cellular and Infection Microbiology. 2012; 2 :83 - 66.
Gupta P, Giri J, Srivastav S, Chande AG, Mukhopadhyaya R, Das PK, et al. Leishmania donovani targets tumor necrosis factor receptor-associated factor (TRAF) 3 for impairing TLR4-mediated host response. The FASEB Journal. 2014; 28 (4):1756-1768 - 67.
Bhattacharya P, Gupta G, Majumder S, Adhikari A, Banerjee S, Halder K, et al. Arabinosylated lipoarabinomannan skews Th2 phenotype towards Th1 during Leishmania infection by chromatin modification: Involvement of MAPK signaling. PLoS One. 2011; 6 (9):e24141 - 68.
Matte C, Descoteaux A. Leishmania donovani amastigotes impair gamma interferon-induced STAT1alpha nuclear translocation by blocking the interaction between STAT1alpha and importin-alpha5. Infection and Immunity. 2010; 78 (9):3736-3743 - 69.
Olivier M, Atayde VD, Isnard A, Hassani K, Shio MT. Leishmania virulence factors: Focus on the metalloprotease GP63. Microbes and Infection. 2012; 14 (15):1377-1389 - 70.
Almeida TF, Palma LC, Mendez LC, Noronha-Dutra AA, Veras PST. Leishmania amazonensis fails to induce the release of reactive oxygen intermediates by CBA macrophages. Parasite Immunology. 2012; 34 (10):492-498 - 71.
Matheoud D, Moradin N, Bellemare-Pelletier A, Shio MT, Hong WJ, Olivier M, et al. Leishmania evades host immunity by inhibiting antigen cross-presentation through direct cleavage of the SNARE VAMP8. Cell Host & Microbe. 2013; 14 (1):15-25 - 72.
Savina A, Jancic C, Hugues S, Guermonprez P, Vargas P, Moura IC, et al. NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells. Cell. 2006; 126 (1):205-218 - 73.
Rybicka JM, Balce DR, Chaudhuri S, Allan ERO, Yates RM. Phagosomal proteolysis in dendritic cells is modulated by NADPH oxidase in a pH-independent manner. The EMBO Journal. 2012; 31 (4):932-944 - 74.
Chakraborty D, Banerjee S, Sen A, Banerjee KK, Das P, Roy S. Leishmania donovani affects antigen presentation of macrophage by disrupting lipid rafts. Journal of Immunology. 2005; 175 (5):3214-3224 - 75.
Ghosh J, Guha R, Das S, Roy S. Liposomal cholesterol delivery activates the macrophage innate immune arm to facilitate intracellular Leishmania donovani killing. Infection and Immunity. 2014; 82 (2):607-617 - 76.
Pinheiro RO, Nunes MP, Pinheiro CS, D’Avila H, Bozza PT, Takiya CM, et al. Induction of autophagy correlates with increased parasite load of Leishmania amazonensis in BALB/c but not C57BL/6 macrophages. Microbes and Infection. 2009; 11 (2):181-190 - 77.
Cyrino LT, Araújo AP, Joazeiro PP, Vicente CP, Giorgio S. In vivo and in vitro Leishmania amazonensis infection induces autophagy in macrophages. Tissue & Cell. 2012; 44 (6):401-408 - 78.
Zarley JH, Britigan BE, Wilson ME. Hydrogen peroxide-mediated toxicity for Leishmania donovani chagasi promastigotes. Role of hydroxyl radical and protection by heat shock. The Journal of Clinical Investigation. 1991; 88 (5):1511-1521 - 79.
Gantt KR, Goldman TL, McCormick ML, Miller MA, Jeronimo SM, Nascimento ET, et al. Oxidative responses of human and murine macrophages during phagocytosis of Leishmania chagasi. Journal of Immunology. 2001; 167 (2):893-901 - 80.
Tovar J, Wilkinson S, Mottram JC, Fairlamb AH. Evidence that trypanothione reductase is an essential enzyme in Leishmania by targeted replacement of the tryA gene locus. Molecular Microbiology. 1998; 29 (2):653-660 - 81.
Barr SD, Gedamu L. Cloning and characterization of three differentially expressed peroxidoxin genes from Leishmania chagasi. Evidence for an enzymatic detoxification of hydroxyl radicals. The Journal of Biological Chemistry. 2001; 276 (36):34279-34287 - 82.
Ghosh S, Goswami S, Adhya S. Role of superoxide dismutase in survival of Leishmania within the macrophage. The Biochemical Journal. 2003; 369 (Pt 3):447-452 - 83.
Plewes KA, Barr SD, Gedamu L. Iron superoxide dismutases targeted to the glycosomes of Leishmania chagasi are important for survival. Infection and Immunity. 2003; 71 (10):5910-5920 - 84.
Miller MA, McGowan SE, Gantt KR, Champion M, Novick SL, Andersen KA, et al. Inducible resistance to oxidant stress in the protozoan Leishmania chagasi. The Journal of Biological Chemistry. 2000; 275 (43):33883-33889 - 85.
Dremier S, Kopperud R, Doskeland SO, Dumont JE, Maenhaut C. Search for new cyclic AMP-binding proteins. FEBS Letters. 2003; 546 (1):103-107 - 86.
Hansen BD, Chiang PK, Perez-Arbelo J. Evidence for a membrane adenosine receptor in Leishmania mexicana mexicana (WR 227). Advances in Experimental Medicine and Biology. 1986; 195 (Pt B):547-551 - 87.
Mancini PE, Patton CL. Cyclic 3′,5′-adenosine monophosphate levels during the developmental cycle of Trypanosoma brucei brucei in the rat. Molecular and Biochemical Parasitology. 1981; 3 (1):19-31 - 88.
Rangel-Aldao R, Allende O, Triana F, Piras R, Henriquez D, Piras M. Possible role of cAMP in the differentiation of Trypanosoma cruzi. Molecular and Biochemical Parasitology. 1987; 22 (1):39-43 - 89.
Sanchez MA, Zeoli D, Klamo EM, Kavanaugh MP, Landfear SM. A family of putative receptor-adenylate cyclases from Leishmania donovani. The Journal of Biological Chemistry. 1995; 270 (29):17551-17558 - 90.
Seebeck T, Schaub R, Johner A. cAMP signalling in the kinetoplastid protozoa. Current Molecular Medicine. 2004; 4 (6):585-599 - 91.
Saha A, Biswas A, Srivastav S, Mukherjee M, Das PK, Ukil A. Prostaglandin E2 negatively regulates the production of inflammatory cytokines/chemokines and IL-17 in visceral leishmaniasis. Journal of Immunology. 2014; 193 (5):2330-2339 - 92.
Conti M, Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: Essential components in cyclic nucleotide signaling. Annual Review of Biochemistry. 2007; 76 :481-511 - 93.
Bhattacharya A, Biswas A, Das PK. Role of a differentially expressed cAMP phosphodiesterase in regulating the induction of resistance against oxidative damage in Leishmania donovani. Free Radical Biology & Medicine. 2009; 47 (10):1494-1506 - 94.
Gettys TW, Vine AJ, Simonds MF, Corbin JD. Activation of the particulate low km phosphodiesterase of adipocytes by addition of cAMP-dependent protein kinase. The Journal of Biological Chemistry. 1988; 263 (21):10359-10363 - 95.
Mochly-Rosen D. Localization of protein kinases by anchoring proteins: A theme in signal transduction. Science. 1995; 268 (5208):247-251 - 96.
Mukhopadhyay NK, Saha AK, Lovelace JK, Da Silva R, Sacks DL, Glew RH. Comparison of the protein kinase and acid phosphatase activities of five species of Leishmania. The Journal of Protozoology. 1988; 35 (4):601-607 - 97.
Bhattacharya A, Biswas A, Das PK. Identification of a protein kinase a regulatory subunit from Leishmania having importance in metacyclogenesis through induction of autophagy. Molecular Microbiology. 2012; 83 (3):548-564 - 98.
Tagoe DNA, Kalejaiye TD, de Koning HP. The ever unfolding story of cAMP signaling in trypanosomatids: Vive la difference! Frontiers in Pharmacology. 2015; 6 :185