Abstract:Lung disease is regularly reported in human filarial infections but the molecular pathogenesis of pulmonary filariasis is poorly understood. We used Litomosoides sigmodontis, a rodent filaria residing in the pleural cavity responsible for pleural inflammation, to model responses to human filarial infections and probe the mechanisms. Wild-type and Th2-deficient mice (ΔdblGata1 and Il-4receptor(r)a -/-/IL-5 -/-) were infected with L. sigmodontis. Survival and growth of adult filariae and prevalence and density o… Show more
“…Microfilaremic load was correlated to the adult filarial load ( r = 0.81, P < 0.0001). In contrast with what was observed in BALB/c mice [ 24 ], amicrofilaremic gerbils (Mf neg ) had significantly fewer parasites in the pleural cavity (Mf neg : n = 2.7 ± 0.78; Mf pos : n = 11.1 ±1.13; t (24) = 4.32, P = 0.0002). Fig.…”
Section: Resultscontrasting
confidence: 75%
“…The infection is cleared in subcutaneous-inoculated mice about 100 days post-infection [ 22 ], whereas it can persist for more than a year in gerbils [ 16 , 23 ]. Microfilariae appear in peripheral blood 8 weeks after infection in about half of infected BALB/c mice and around 9–12 weeks after infection in about 70–90% of infected gerbils [ 16 , 18 , 24 – 26 ].…”
Section: Introductionmentioning
confidence: 99%
“…The proliferation and the alternative activation of these pleural macrophages is promoted by the interleukin (IL)-4 receptor and IL-33 (ST2) in L. sigmodontis infected BALB/c mice [ 32 ]. The alteration of IL-4/IL-5 signalling alters this cellular environment and leads to increased susceptibility to L. sigmodontis infection and influences adult worm burden and/or microfilaremia [ 24 , 33 , 34 ] as well as lung pathogenesis [ 24 , 33 ]. Particularly, a central role of IL-13 and IL-4 in macrophage activation and eosinophil recruitment and in lung pathogenesis has been highlighted in a recent analysis of cytokine and chemokine transcripts in the lungs of 70 days-infected BALB/c mice [ 24 ].…”
Section: Introductionmentioning
confidence: 99%
“…The alteration of IL-4/IL-5 signalling alters this cellular environment and leads to increased susceptibility to L. sigmodontis infection and influences adult worm burden and/or microfilaremia [ 24 , 33 , 34 ] as well as lung pathogenesis [ 24 , 33 ]. Particularly, a central role of IL-13 and IL-4 in macrophage activation and eosinophil recruitment and in lung pathogenesis has been highlighted in a recent analysis of cytokine and chemokine transcripts in the lungs of 70 days-infected BALB/c mice [ 24 ]. Some lung pathology was also partially described in cotton rats, gerbils and white rats [ 19 , 20 , 35 ] showing a cellular and fibrotic reaction on the outside of the lung pleura.…”
Section: Introductionmentioning
confidence: 99%
“…However there was no evidence that the findings in these rodents were dependent on the microfilariae. We recently showed that lung pathology in L. sigmodontis -infected BALB/c mice is dependent on microfilariae and Th2 immune responses [ 24 ]. Here we further describe the pulmonary pleural pathology in L. sigmodontis- infected gerbils Meriones unguiculatus and discuss the role of microfilariae in the development of lung inflammation.…”
Background
Pulmonary manifestations are regularly reported in both human and animal filariasis. In human filariasis, the main known lung manifestations are the tropical pulmonary eosinophilia syndrome. Its duration and severity are correlated with the presence of microfilariae. Litomosoides sigmodontis is a filarial parasite residing in the pleural cavity of rodents. This model is widely used to understand the immune mechanisms that are established during infection and for the screening of therapeutic molecules. Some pulmonary manifestations during the patent phase of infection with L. sigmodontis have been described in different rodent hosts more or less permissive to infection.
Methods
Here, the permissive Mongolian gerbil (Meriones unguiculatus) was infected with L. sigmodontis. Prevalence and density of microfilariae and adult parasites were evaluated. Lungs were analyzed for pathological signatures using immunohistochemistry and 3D imaging techniques (two-photon and light sheet microscopy).
Results
Microfilaremia in gerbils was correlated with parasite load, as amicrofilaremic individuals had fewer parasites in their pleural cavities. Fibrotic polypoid structures were observed on both pleurae of infected gerbils. Polyps were of variable size and developed from the visceral mesothelium over the entire pleura. The larger polyps were vascularized and strongly infiltrated by immune cells such as eosinophils, macrophages or lymphocytes. The formation of these structures was induced by the presence of adult filariae since small and rare polyps were observed before patency, but they were exacerbated by the presence of gravid females and microfilariae.
Conclusions
Altogether, these data emphasize the role of host-specific factors in the pathogenesis of filarial infections.
“…Microfilaremic load was correlated to the adult filarial load ( r = 0.81, P < 0.0001). In contrast with what was observed in BALB/c mice [ 24 ], amicrofilaremic gerbils (Mf neg ) had significantly fewer parasites in the pleural cavity (Mf neg : n = 2.7 ± 0.78; Mf pos : n = 11.1 ±1.13; t (24) = 4.32, P = 0.0002). Fig.…”
Section: Resultscontrasting
confidence: 75%
“…The infection is cleared in subcutaneous-inoculated mice about 100 days post-infection [ 22 ], whereas it can persist for more than a year in gerbils [ 16 , 23 ]. Microfilariae appear in peripheral blood 8 weeks after infection in about half of infected BALB/c mice and around 9–12 weeks after infection in about 70–90% of infected gerbils [ 16 , 18 , 24 – 26 ].…”
Section: Introductionmentioning
confidence: 99%
“…The proliferation and the alternative activation of these pleural macrophages is promoted by the interleukin (IL)-4 receptor and IL-33 (ST2) in L. sigmodontis infected BALB/c mice [ 32 ]. The alteration of IL-4/IL-5 signalling alters this cellular environment and leads to increased susceptibility to L. sigmodontis infection and influences adult worm burden and/or microfilaremia [ 24 , 33 , 34 ] as well as lung pathogenesis [ 24 , 33 ]. Particularly, a central role of IL-13 and IL-4 in macrophage activation and eosinophil recruitment and in lung pathogenesis has been highlighted in a recent analysis of cytokine and chemokine transcripts in the lungs of 70 days-infected BALB/c mice [ 24 ].…”
Section: Introductionmentioning
confidence: 99%
“…The alteration of IL-4/IL-5 signalling alters this cellular environment and leads to increased susceptibility to L. sigmodontis infection and influences adult worm burden and/or microfilaremia [ 24 , 33 , 34 ] as well as lung pathogenesis [ 24 , 33 ]. Particularly, a central role of IL-13 and IL-4 in macrophage activation and eosinophil recruitment and in lung pathogenesis has been highlighted in a recent analysis of cytokine and chemokine transcripts in the lungs of 70 days-infected BALB/c mice [ 24 ]. Some lung pathology was also partially described in cotton rats, gerbils and white rats [ 19 , 20 , 35 ] showing a cellular and fibrotic reaction on the outside of the lung pleura.…”
Section: Introductionmentioning
confidence: 99%
“…However there was no evidence that the findings in these rodents were dependent on the microfilariae. We recently showed that lung pathology in L. sigmodontis -infected BALB/c mice is dependent on microfilariae and Th2 immune responses [ 24 ]. Here we further describe the pulmonary pleural pathology in L. sigmodontis- infected gerbils Meriones unguiculatus and discuss the role of microfilariae in the development of lung inflammation.…”
Background
Pulmonary manifestations are regularly reported in both human and animal filariasis. In human filariasis, the main known lung manifestations are the tropical pulmonary eosinophilia syndrome. Its duration and severity are correlated with the presence of microfilariae. Litomosoides sigmodontis is a filarial parasite residing in the pleural cavity of rodents. This model is widely used to understand the immune mechanisms that are established during infection and for the screening of therapeutic molecules. Some pulmonary manifestations during the patent phase of infection with L. sigmodontis have been described in different rodent hosts more or less permissive to infection.
Methods
Here, the permissive Mongolian gerbil (Meriones unguiculatus) was infected with L. sigmodontis. Prevalence and density of microfilariae and adult parasites were evaluated. Lungs were analyzed for pathological signatures using immunohistochemistry and 3D imaging techniques (two-photon and light sheet microscopy).
Results
Microfilaremia in gerbils was correlated with parasite load, as amicrofilaremic individuals had fewer parasites in their pleural cavities. Fibrotic polypoid structures were observed on both pleurae of infected gerbils. Polyps were of variable size and developed from the visceral mesothelium over the entire pleura. The larger polyps were vascularized and strongly infiltrated by immune cells such as eosinophils, macrophages or lymphocytes. The formation of these structures was induced by the presence of adult filariae since small and rare polyps were observed before patency, but they were exacerbated by the presence of gravid females and microfilariae.
Conclusions
Altogether, these data emphasize the role of host-specific factors in the pathogenesis of filarial infections.
Filariae are vector-borne parasitic nematodes that are endemic worldwide, in tropical and subtropical regions. Important human filariae spp. include Onchocerca volvulus, Wuchereria bancrofti and Brugia spp., and Loa loa and Mansonella spp. causing onchocerciasis (river blindness), lymphatic filariasis (lymphedema and hydrocele), loiasis (eye worm), and mansonelliasis, respectively. It is estimated that over 1 billion individuals live in endemic regions where filarial diseases are a public health concern contributing to significant disability adjusted life years (DALYs). Thus, efforts to control and eliminate filarial diseases were already launched by the WHO in the 1970s, especially against lymphatic filariasis and onchocerciasis, and are mainly based on mass drug administration (MDA) of microfilaricidal drugs (ivermectin, diethylcarbamazine, albendazole) to filarial endemic areas accompanied with vector control strategies with the goal to reduce the transmission. With the United Nations Sustainable Development Goals (SDGs), it was decided to eliminate transmission of onchocerciasis and stop lymphatic filariasis as a public health problem by 2030. It was also requested that novel drugs and treatment strategies be developed. Mouse models provide an important platform for anti-filarial drug research in a preclinical setting. This review presents an overview about the Litomosoides sigmodontis and Acanthocheilonema viteae filarial mouse models and their role in immunological research as well as preclinical studies about novel anti-filarial drugs and treatment strategies.
Among vector-borne helminths, filarioids of the genus Dipetalonema (Spirurida: Onchocercidae) localize in several tissues and body cavities of several animal species, causing mild to moderate lesions. The pathological findings associated with Dipetalonema spp. infection in Neotropical monkeys from southern Brazil are herein described, along with a fatal case due to filarial polyserositis and entrapment of an intestinal segment. At necropsy, nematodes were observed in abdominal and thoracic cavities, or in the pericardium of 37 (31.3%) out of the 118 individuals examined (i.e., 35 Alouatta guariba clamitans and two Sapajus nigritus). In addition, at histology, 27.0% of positive animals presented microfilarie (inside blood vessels of lung, spleen, liver, and brain) and 8.1% presented adult nematodes in the heart, lung, and liver. In two cases, cross-sections of filarioids were associated with areas of epicardial thickening with intense fibrosis and pyogranulomatous inflammation in the brain, heart, liver, lungs, or spleen. The DNA fragment was amplify using the cox1 gene, sequenced and analyzed to identify the nematode species collected; presence of Wolbachia was assessed in the filarioids using the 16S rRNA gene. At BLAST analysis of the cox1 gene, 10 sequences showed 91.7% nucleotide identity with Dipetalonema gracile, and two with D. gracile (98.5%) and Dipetalonema graciliformis (98.3%). Phylogenetic analyses clustered sequences of the cox1 obtained in this study in two clades corresponding with the host species. Wolbachia sp. endosymbiont was detected in four samples. Data herein reported provide a description of pathological lesions associated with the infection by Dipetalonema spp., suggesting that they may cause disease in Neotropical monkeys. In addition, a better understanding of diversity and biology of Dipetalonema spp. in South America is needed to assess the impact they may cause in native non-human primates from Brazil.
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