Stimulator of interferon genes (STING) was initially described as a sensor of intracellular bacterial and viral DNA and a promising adjuvant target in innate immune cells; more recently STING has ...also been shown to detect endogenous DNA and play a role in tumor immunity and autoimmune disease development. Thus far STING has been studied in macrophages and dendritic cells. In this study, to our knowledge we provide the first evidence of STING activation in T cells, in which STING agonists not only provoke type I IFN production and IFN-stimulated gene expression, mirroring the response of innate cells, but are also capable of activating cell stress and death pathways. Our results suggest a re-evaluation of STING agonist-based therapies may be necessary to identify the possible effects on the T cell compartment. Conversely, the effects of STING on T cells could potentially be harnessed for therapeutic applications.
Ixodes ticks maintain a large and diverse array of human pathogens in the enzootic cycle, including Borrelia burgdorferi and Babesia microti . Despite the poor ecological fitness of B. microti , ...babesiosis has recently emerged in areas endemic for Lyme disease. Studies in ticks, reservoir hosts, and humans indicate that coinfection with B. burgdorferi and B. microti is common, promotes transmission and emergence of B. microti in the enzootic cycle, and causes greater disease severity and duration in humans. These interdisciplinary studies may serve as a paradigm for the study of other vector-borne coinfections. Identifying ecological drivers of pathogen emergence and host factors that fuel disease severity in coinfected individuals will help guide the design of effective preventative and therapeutic strategies.
Babesiosis Vannier, Edouard G; Diuk-Wasser, Maria A; Ben Mamoun, Choukri ...
Infectious disease clinics of North America,
06/2015, Letnik:
29, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Babesiosis is caused by intraerythrocytic protozoan parasites that are transmitted by ticks, or less commonly through blood transfusion or transplacentally. Human babesiosis was first recognized in a ...splenectomized patient in Europe but most cases have been reported from the northeastern and upper midwestern United States in people with an intact spleen and no history of immune impairment. Cases are reported in Asia, Africa, Australia, Europe, and South America. Babesiosis shares many clinical features with malaria and can be fatal, particularly in the elderly and the immunocompromised.
Babesia microti and Borrelia burgdorferi, the respective causative agents of human babesiosis and Lyme disease, are maintained in their enzootic cycles by the blacklegged tick (Ixodes scapularis) and ...use the white-footed mouse (Peromyscus leucopus) as primary reservoir host. The geographic range of both pathogens has expanded in the United States, but the spread of babesiosis has lagged behind that of Lyme disease. Several studies have estimated the basic reproduction number (R0) for B. microti to be below the threshold for persistence (<1), a finding that is inconsistent with the persistence and geographic expansion of this pathogen. We tested the hypothesis that host coinfection with B. burgdorferi increases the likelihood of B. microti transmission and establishment in new areas. We fed I. scapularis larva on P. leucopus mice that had been infected in the laboratory with B. microti and/or B. burgdorferi. We observed that coinfection in mice increases the frequency of B. microti infected ticks. To identify the ecological variables that would increase the probability of B. microti establishment in the field, we integrated our laboratory data with field data on tick burden and feeding activity in an R0 model. Our model predicts that high prevalence of B. burgdorferi infected mice lowers the ecological threshold for B. microti establishment, especially at sites where larval burden on P. leucopus is lower and where larvae feed simultaneously or soon after nymphs infect mice, when most of the transmission enhancement due to coinfection occurs. Our studies suggest that B. burgdorferi contributes to the emergence and expansion of B. microti and provides a model to predict the ecological factors that are sufficient for emergence of B. microti in the wild.
Abstract
Background
Persistent and relapsing babesiosis caused by Babesia microti often occurs in immunocompromised patients, and has been associated with resistance to antimicrobial agents such as ...atovaquone. Given the rising incidence of babesiosis in the United States, novel drugs are urgently needed. In the current study, we tested whether clofazimine (CFZ), an antibiotic used to treat leprosy and drug-resistant tuberculosis, is effective against B. microti.
Methods
Mice with severe combined immunodeficiency were infected with 107B. microti–infected erythrocytes. Parasites were detected by means of microscopic examination of Giemsa-stained blood smears or nested polymerase chain reaction. CFZ was administered orally.
Results
Uninterrupted monotherapy with CFZ curtailed the rise of parasitemia and achieved radical cure. B. microti parasites and B. microti DNA were cleared by days 10 and 50 of therapy, respectively. A 7-day administration of CFZ delayed the rise of parasitemia by 22 days. This rise was caused by B. microti isolates that did not carry mutations in the cytochrome b gene. Accordingly, a 14-day administration of CFZ was sufficient to resolve high-grade parasitemia caused by atovaquone-resistant B. microti parasites.
Conclusions
Clofazimine is effective against B. microti infection in the immunocompromised host. Additional preclinical studies are required to identify the minimal dose and dosage of CFZ for babesiosis.
Clofazimine (CFZ) is approved for the treatment of leprosy and is being repurposed for multidrug-resistant tuberculosis. This report establishes that CFZ monotherapy eradicates Babesia microti infection in immunocompromised mice. CFZ also resolves high-grade parasitemia caused by atovaquone-resistant B. microti parasites.
Human babesiosis Vannier, Edouard; Gewurz, Benjamin E; Krause, Peter J
Infectious disease clinics of North America,
09/2008, Letnik:
22, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Human babesiosis is an emerging intraerythrocytic infection caused by protozoal parasites transmitted by ixodid ticks. Babesiosis is endemic in the northeastern and upper midwestern regions of the ...United States and is found sporadically in other parts of the United States, Europe, Asia, Africa, and South America. Babesial infections range from asymptomatic to severe and occasionally are fatal. Specific laboratory diagnosis of babesial infection is made by morphologic examination of Giemsa-stained blood smears, serology, and amplification of babesial DNA using polymerase chain reaction. The combination of atovaquone and azithromycin is the treatment of choice for mild-to-moderate illness, whereas clindamycin and quinine and exchange transfusion are indicated for severe disease.
The pathobiology of malaria has been extensively studied in humans but many questions remain, especially regarding fulminant disease associated with Plasmodium falciparum infection. Babesiosis, ...recognized since biblical times as an important disease of livestock and more recently as an emerging health problem in humans, is caused by related intraerythrocytic protozoa with a similar pathogenesis and clinical course. Recent studies of cytokine activation and erythrocyte cytoadherence in babesiosis and malaria have exploited these similarities to provide new insights into malaria pathobiology. Continued investigation of similarities and differences in the pathogenesis of babesiosis and malaria should lead to additional fundamental insights for both conditions.
ABSTRACT
The impact of aging on the cytokine response of human skeletal muscle to exercise‐induced injury remains poorly understood. We enrolled physically active, young (23–35 years old, n=15) and ...old (66–78 years old, n=15) men to perform 45 min of downhill running (16% descent) at 75% VO2max. Biopsies of vastus lateralis were obtained 24 h before and 72 h after acute eccentric exercise. Transcripts for inflammatory (TNF‐α, IL‐1β) and anti‐inflammatory cytokines (IL‐6, TGF‐β1) were quantified by real‐time PCR. Before exercise, cytokine transcripts did not differ with age. At old age, exercise induced a blunted accumulation of transcripts encoding the pan‐leukocyte surface marker CD18 (young: 10.1‐fold increase, P<0.005; old: 4.7‐fold increase, P=0.02; young vs. old: P<0.05). In both age groups, CD18 transcript accumulation strongly correlated with TNF‐α (young, r=0.87, P<0.001; old, r=0.72, P=0.002) and TGF‐β1 transcript accumulation (young, r=0.80, P<0.001; old, r=0.64, P=0.008). At old age, there was no correlation between IL‐1 β and CD18 transcript accumulation. Furthermore, exercise induced IL‐6 transcript accumulation in young (3.6‐fold, P=0.057) but not in old men. Our results suggest that aging impairs the adaptive response of human skeletal muscle to eccentric exercise by differential modulation of a discrete set of inflammatory and anti‐inflammatory cytokine genes.
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