Neutrophils and dendritic cells (DC) converge at sites of acute inflammation in the skin followin... more Neutrophils and dendritic cells (DC) converge at sites of acute inflammation in the skin following pathogen deposition by the bites of arthropod vectors or by needle injection. How neutrophils might interact with and modulate the function of DCs in these inflammatory settings has not been previously addressed. Neutrophils are the predominant recruited and infected cells during the earliest stage of Leishmania major infection in the skin. The infected neutrophils recovered from the skin expressed elevated levels of apoptotic markers and were preferentially captured by dermal DCs, the majority of which acquired their parasites via uptake of infected neutrophils. Neutrophil depletion augmented the expression of activation markers on infected DCs and their ability to present Leishmania antigen ex vivo, and markedly enhanced CD4+ T cell priming against parasite-derived antigen in vivo. The findings suggest that L. major exploits the apoptotic cell clearance function of DCs to suppress the development of acquired resistance until the acute neutrophilic response is resolved.
Clearance of apoptotic exudate neutrophils (efferocytosis) induces either pro- or anti-inflammato... more Clearance of apoptotic exudate neutrophils (efferocytosis) induces either pro- or anti-inflammatory responses in mouse macrophages depending on host genetic background. In this study, we investigated whether neutrophil efferocytosis induces a stable macrophage phenotype that could be recalled by late restimulation with LPS. Bone marrow-derived macrophages previously stimulated by pro- but not anti-inflammatory neutrophil efferocytosis expressed a regulatory/M2b phenotype characterized by low IL-12 and high IL-10 production following restimulation, increased expression of LIGHT/TNF superfamily 14, Th2-biased T cell responses, and permissive replication of Leishmania major. Induction of regulatory/M2b macrophages required neutrophil elastase activity and was partially dependent on TLR4 signaling. These results suggested that macrophage differentiation to a regulatory phenotype plays a role in resolution of inflammation but could contribute to increased humoral Ab responses and parasit...
Malaria and leishmaniasis are endemic parasitic diseases in tropical and subtropical countries. A... more Malaria and leishmaniasis are endemic parasitic diseases in tropical and subtropical countries. Although the overlap of these diseases in the same host is frequently described, co-infection remains a neglected issue in the medical and scientific community. The complex relationship of concomitant infections with Plasmodium spp. and Leishmania spp. is highlighted in studies of natural and experimental co-infections, showing how this “dual” infection can exacerbate or suppress an effective immune response to these protozoa. Thus, a Plasmodium infection preceding or following Leishmania infection can impact the clinical course, accurate diagnosis, and management of leishmaniasis, and vice versa. The concept that in nature we are affected by concomitant infections reinforces the need to address the theme and ensure its due importance. In this review we explore and describe the studies available in the literature on Plasmodium spp. and Leishmania spp. co-infection, the scenarios, and the ...
Data recently reported by our group indicate that stimulation with a pool of immunogens capable o... more Data recently reported by our group indicate that stimulation with a pool of immunogens capable of eliciting type 2 immune responses can restore the cognitive and behavioral dysfunctions recorded after a single episode of non-severe rodent malaria caused by Plasmodium berghei ANKA. Here we explored the hypothesis that isolated immunization with one of the type 2 immune response-inducing immunogens, the human diphtheria-tetanus (dT) vaccine, may revert damages associated with malaria. To investigate this possibility, we studied the dynamics of cognitive deficits and anxiety-like phenotype following non-severe experimental malaria and evaluated the effects of immunization with both dT and of a pool of type 2 immune stimuli in reversing these impairments. Locomotor activity and long-term memory deficits were assessed through the open field test (OFT) and novel object recognition task (NORT), while the anxiety-like phenotype was assessed by OFT and light/dark task (LDT). Our results ind...
Pathological features observed in both human and experimental cerebral malaria (ECM) are endothel... more Pathological features observed in both human and experimental cerebral malaria (ECM) are endothelial dysfunction and changes in blood components. Blood transfusion has been routinely used in patients with severe malarial anemia and can also benefit comatose and acidotic malaria patients. In the present study Plasmodium berghei-infected mice were transfused intraperitoneally with 200 μL of whole blood along with 20 mg/kg of artemether. ECM mice showed severe thrombocytopenia and decreases in hematocrit. Artemether treatment markedly aggravated anemia within 24 h. Whole blood administration significantly prevented further drop in hematocrit and partially restored the platelet count. Increased levels of plasma angiopoietin-2 (Ang-2) remained high 24 h after artemether treatment but returned to normal levels 24 h after blood transfusion, indicating reversal to quiescence. Ang-1 was depleted in ECM mice and levels were not restored by any treatment. Blood transfusion prevented the aggrav...
Inflammatory monocytes can be manipulated by environmental cues to perform multiple functions. To... more Inflammatory monocytes can be manipulated by environmental cues to perform multiple functions. To define the role of monocytes during primary or secondary infection with an intra-phagosomal pathogen we employed Leishmania major-red fluorescent protein (RFP) parasites and multi-color flow cytometry to define and enumerate infected and uninfected inflammatory cells in the skin. During primary infection, infected monocytes had altered maturation and were the initial mononuclear host cell for parasite replication. In contrast, at a distal site of secondary infection in mice with a healed but persistent primary infection, this same population rapidly produced inducible nitric oxide synthase (iNOS) in an IFN-γ dependent manner and was critical for parasite killing. Maturation to a dendritic cell-like phenotype was not required for monocyte iNOS-production, and enhanced monocyte recruitment correlated with IFN-γ dependent cxcl10 expression. In contrast, neutrophils appeared to be a safe ha...
Macrophages - Celebrating 140 Years of Discovery [Working Title]
Macrophage phenotypes, such as macrophage (M) 1 (classically activated macrophage) and M2 (altern... more Macrophage phenotypes, such as macrophage (M) 1 (classically activated macrophage) and M2 (alternatively activated macrophage), determine the macrophage role as an effector immune cell or as a permissive host for the intracellular pathogenic protozoan Leishmania spp. Leishmania parasites and the host immune system shape macrophage phenotypes, which in turn can help parasite control or promote infection. Here, we discussed how shifting macrophage phenotypes might change disease outcome in leishmaniasis, by addressing: (1) macrophage phenotypes in leishmaniasis; (2) the functional phenotypes of resident and inflammatory macrophages; (3) the interplay with neutrophils modulates macrophage function; (4) the crosstalk with T cells shapes macrophage phenotypes; and (5) potential therapeutic tools to skew macrophage phenotypes and disease outcomes.
with apoptotic but not with necrotic neutrophils increase parasite burden in human macrophages in... more with apoptotic but not with necrotic neutrophils increase parasite burden in human macrophages infected
Neutrophils and dendritic cells (DC) converge at sites of acute inflammation in the skin followin... more Neutrophils and dendritic cells (DC) converge at sites of acute inflammation in the skin following pathogen deposition by the bites of arthropod vectors or by needle injection. How neutrophils might interact with and modulate the function of DCs in these inflammatory settings has not been previously addressed. Neutrophils are the predominant recruited and infected cells during the earliest stage of Leishmania major infection in the skin. The infected neutrophils recovered from the skin expressed elevated levels of apoptotic markers and were preferentially captured by dermal DCs, the majority of which acquired their parasites via uptake of infected neutrophils. Neutrophil depletion augmented the expression of activation markers on infected DCs and their ability to present Leishmania antigen ex vivo, and markedly enhanced CD4+ T cell priming against parasite-derived antigen in vivo. The findings suggest that L. major exploits the apoptotic cell clearance function of DCs to suppress the development of acquired resistance until the acute neutrophilic response is resolved.
Clearance of apoptotic exudate neutrophils (efferocytosis) induces either pro- or anti-inflammato... more Clearance of apoptotic exudate neutrophils (efferocytosis) induces either pro- or anti-inflammatory responses in mouse macrophages depending on host genetic background. In this study, we investigated whether neutrophil efferocytosis induces a stable macrophage phenotype that could be recalled by late restimulation with LPS. Bone marrow-derived macrophages previously stimulated by pro- but not anti-inflammatory neutrophil efferocytosis expressed a regulatory/M2b phenotype characterized by low IL-12 and high IL-10 production following restimulation, increased expression of LIGHT/TNF superfamily 14, Th2-biased T cell responses, and permissive replication of Leishmania major. Induction of regulatory/M2b macrophages required neutrophil elastase activity and was partially dependent on TLR4 signaling. These results suggested that macrophage differentiation to a regulatory phenotype plays a role in resolution of inflammation but could contribute to increased humoral Ab responses and parasit...
Malaria and leishmaniasis are endemic parasitic diseases in tropical and subtropical countries. A... more Malaria and leishmaniasis are endemic parasitic diseases in tropical and subtropical countries. Although the overlap of these diseases in the same host is frequently described, co-infection remains a neglected issue in the medical and scientific community. The complex relationship of concomitant infections with Plasmodium spp. and Leishmania spp. is highlighted in studies of natural and experimental co-infections, showing how this “dual” infection can exacerbate or suppress an effective immune response to these protozoa. Thus, a Plasmodium infection preceding or following Leishmania infection can impact the clinical course, accurate diagnosis, and management of leishmaniasis, and vice versa. The concept that in nature we are affected by concomitant infections reinforces the need to address the theme and ensure its due importance. In this review we explore and describe the studies available in the literature on Plasmodium spp. and Leishmania spp. co-infection, the scenarios, and the ...
Data recently reported by our group indicate that stimulation with a pool of immunogens capable o... more Data recently reported by our group indicate that stimulation with a pool of immunogens capable of eliciting type 2 immune responses can restore the cognitive and behavioral dysfunctions recorded after a single episode of non-severe rodent malaria caused by Plasmodium berghei ANKA. Here we explored the hypothesis that isolated immunization with one of the type 2 immune response-inducing immunogens, the human diphtheria-tetanus (dT) vaccine, may revert damages associated with malaria. To investigate this possibility, we studied the dynamics of cognitive deficits and anxiety-like phenotype following non-severe experimental malaria and evaluated the effects of immunization with both dT and of a pool of type 2 immune stimuli in reversing these impairments. Locomotor activity and long-term memory deficits were assessed through the open field test (OFT) and novel object recognition task (NORT), while the anxiety-like phenotype was assessed by OFT and light/dark task (LDT). Our results ind...
Pathological features observed in both human and experimental cerebral malaria (ECM) are endothel... more Pathological features observed in both human and experimental cerebral malaria (ECM) are endothelial dysfunction and changes in blood components. Blood transfusion has been routinely used in patients with severe malarial anemia and can also benefit comatose and acidotic malaria patients. In the present study Plasmodium berghei-infected mice were transfused intraperitoneally with 200 μL of whole blood along with 20 mg/kg of artemether. ECM mice showed severe thrombocytopenia and decreases in hematocrit. Artemether treatment markedly aggravated anemia within 24 h. Whole blood administration significantly prevented further drop in hematocrit and partially restored the platelet count. Increased levels of plasma angiopoietin-2 (Ang-2) remained high 24 h after artemether treatment but returned to normal levels 24 h after blood transfusion, indicating reversal to quiescence. Ang-1 was depleted in ECM mice and levels were not restored by any treatment. Blood transfusion prevented the aggrav...
Inflammatory monocytes can be manipulated by environmental cues to perform multiple functions. To... more Inflammatory monocytes can be manipulated by environmental cues to perform multiple functions. To define the role of monocytes during primary or secondary infection with an intra-phagosomal pathogen we employed Leishmania major-red fluorescent protein (RFP) parasites and multi-color flow cytometry to define and enumerate infected and uninfected inflammatory cells in the skin. During primary infection, infected monocytes had altered maturation and were the initial mononuclear host cell for parasite replication. In contrast, at a distal site of secondary infection in mice with a healed but persistent primary infection, this same population rapidly produced inducible nitric oxide synthase (iNOS) in an IFN-γ dependent manner and was critical for parasite killing. Maturation to a dendritic cell-like phenotype was not required for monocyte iNOS-production, and enhanced monocyte recruitment correlated with IFN-γ dependent cxcl10 expression. In contrast, neutrophils appeared to be a safe ha...
Macrophages - Celebrating 140 Years of Discovery [Working Title]
Macrophage phenotypes, such as macrophage (M) 1 (classically activated macrophage) and M2 (altern... more Macrophage phenotypes, such as macrophage (M) 1 (classically activated macrophage) and M2 (alternatively activated macrophage), determine the macrophage role as an effector immune cell or as a permissive host for the intracellular pathogenic protozoan Leishmania spp. Leishmania parasites and the host immune system shape macrophage phenotypes, which in turn can help parasite control or promote infection. Here, we discussed how shifting macrophage phenotypes might change disease outcome in leishmaniasis, by addressing: (1) macrophage phenotypes in leishmaniasis; (2) the functional phenotypes of resident and inflammatory macrophages; (3) the interplay with neutrophils modulates macrophage function; (4) the crosstalk with T cells shapes macrophage phenotypes; and (5) potential therapeutic tools to skew macrophage phenotypes and disease outcomes.
with apoptotic but not with necrotic neutrophils increase parasite burden in human macrophages in... more with apoptotic but not with necrotic neutrophils increase parasite burden in human macrophages infected
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