Toxoplasma gondii-Induced Long-Term Changes in the Upper Intestinal Microflora during the Chronic Stage of Infection

Toxoplasma gondiiis an obligate intracellular parasite with worldwide distribution. Felines are the definitive hosts supporting the complete life cycle ofT. gondii.However, other warm-blooded animals such as rodents and humans can also be infected. Infection of such secondary hosts results in long-term infection characterized by the presence of tissue cysts in the brain and other organs. While it is known thatT. gondiiinfection in rodents is associated with behavioral changes, the mechanisms behind these changes remain unclear. Alterations of the host intestinal microflora are recognized as a prominent role player in shaping host behavior and cognition. It has been shown that acuteT. gondiiinfection of mice results in microflora changes as a result of gastrointestinal inflammation in inbred mouse models. The long-term effects of chronicT. gondiiinfection on microbial communities, however, are unknown. In this study, after we verified using our model in terms of measuring microflora changes during an acute episode of toxoplasmosis, we assessed the microbiome changes that occur during a long-term infection; then we further investigated these changes in a follow-up study of chronic infection. These analyses were performed by constructing and sequencing 16S rRNA amplicon DNA libraries from small intestine fecal specimens. We found that acute infection with the GT1 strain ofT. gondiicaused an enrichment of Bacteroidetes compared with controls in CD1 mice. Strikingly, this enrichment upheld throughout long-term chronic infection. The potential biological consequences of this alteration in rodents and humans should be subjected to further exploration.

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Evaluation of current and emerging anti-malarial medicines for inhibition of Toxoplasma gondii growth in vitro

10.1101/316455 ◽

2018 ◽

Author(s):

Joshua B. Radke ◽

Jeremy N. Burrows ◽

Daniel E. Goldberg ◽

L. David Sibley

Keyword(s):

Toxoplasma Gondii ◽

Chronic Infection ◽

Acute Infection ◽

In Vitro Growth ◽

Zoonotic Infection ◽

Adverse Side Effects ◽

Folate Pathway ◽

Current Therapies ◽

Serious Disease

AbstractToxoplasma gondii is a common zoonotic infection of humans and estimates indicate that 1-2 billion people are chronically infected. Although largely asymptomatic, chronic infection poses risk of serious disease due to reactivation should immunity decline. Current therapies for toxoplasmosis only control acute infection caused by actively proliferating tachyzoites but do not eradicate the chronic tissue cyst stages. As well, there are considerable adverse side effects of the most commonly used therapy of combined sulfadiazine and pyrimethamine. Targeting the folate pathway is also an effective treatment for malaria, caused by the related parasites Plasmodium spp., suggesting common agents might be used to treat both infections. Here we evaluated currently approved and newly emerging medicines for malaria to determine if such compounds might also prove useful for treating toxoplasmosis. Surprisingly, the majority of anti-malarial compounds being used currently or in development for treatment of malaria were only modestly effective at inhibiting in vitro growth of T. gondii tachyzoites. These findings suggest that many essential processes in P. falciparum that are targeted by anti-malarial compounds are either divergent, or non-essential in T. gondii, thus limiting options for repurposing of current antimalarial medicines for toxoplasmosis.

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Digestive involvement in Long- COVID syndrome

Medicine and Pharmacy Reports ◽

10.15386/mpr-2340 ◽

2021 ◽

Author(s):

Alina M. Bogariu ◽

Dan L. Dumitrascu

Keyword(s):

Chronic Diseases ◽

Observational Studies ◽

Digestive System ◽

Medical Literature ◽

Liver Enzymes ◽

Acute Infection ◽

Gastrointestinal Symptoms ◽

Long Term Effects ◽

Search Terms

Background and aim. The SARS-CoV-2 infection which caused a worldwide epidemic was considered first a lung disease. Later on, it was found that the disease caused by this virus, SARS-CoV-2, can affect most organs, including the digestive system. The long-term effects of this infection are now progressively detected and called Long-COVID. This review aims is to present the updated knowledge of the digestive sequelae after SARS-CoV-2 infection. Methods. A search was performed in the main medical literature databases. The following search terms were used: long-covid, gastrointestinal or gastric sequelae SARS-CoV-2 and COVID-19. Data on gastrointestinal symptoms after 12 weeks were collected and presented. Observational studies were included. Studies that focus only on acute COVID-19 infection (<4 weeks) were excluded. Results. The main symptoms that can occur in the long term are: diarrhea, nausea, vomiting, abdominal pain, along with increased liver enzymes. Patients with chronic diseases have a higher risk of developing long-term sequelae, but it is not documented that digestive sequelae are influenced by the presence of chronic diseases. Conclusions. The SARS-CoV-2 virus can affect any part of the digestive system not only in the acute infection phase but also for longer time, leaving long-term sequelae.

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The Toxoplasma gondii Rhoptry Kinome Is Essential for Chronic Infection

mBio ◽

10.1128/mbio.00193-16 ◽

2016 ◽

Vol 7 (3) ◽

Cited By ~ 36

Author(s):

Barbara A. Fox ◽

Leah M. Rommereim ◽

Rebekah B. Guevara ◽

Alejandra Falla ◽

Miryam Andrea Hortua Triana ◽

...

Keyword(s):

Innate Immunity ◽

Toxoplasma Gondii ◽

Virulence Factors ◽

Chronic Infection ◽

Parasitophorous Vacuole ◽

Acute Infection ◽

Host Cells ◽

Type Ii ◽

Host Manipulation ◽

Parasite Survival

ABSTRACT Ingestion of the obligate intracellular protozoan parasite Toxoplasma gondii causes an acute infection that leads to chronic infection of the host. To facilitate the acute phase of the infection, T. gondii manipulates the host response by secreting rhoptry organelle proteins (ROPs) into host cells during its invasion. A few key ROP proteins with signatures of kinases or pseudokinases (ROPKs) act as virulence factors that enhance parasite survival against host gamma interferon-stimulated innate immunity. However, the roles of these and other ROPK proteins in establishing chronic infection have not been tested. Here, we deleted 26 ROPK gene loci encoding 31 unique ROPK proteins of type II T. gondii and show that numerous ROPK proteins influence the development of chronic infection. Cyst burdens were increased in the Δ rop16 knockout strain or moderately reduced in 11 ROPK knockout strains. In contrast, deletion of ROP5 , ROP17 , ROP18 , ROP35 , or ROP38 / 29 / 19 ( ROP38 , ROP29 , and ROP19 ) severely reduced cyst burdens. Δ rop5 and Δ rop18 knockout strains were less resistant to host immunity-related GTPases (IRGs) and exhibited >100-fold-reduced virulence. ROP18 kinase activity and association with the parasitophorous vacuole membrane were necessary for resistance to host IRGs. The Δ rop17 strain exhibited a >12-fold defect in virulence; however, virulence was not affected in the Δ rop35 or Δ rop38 / 29 / 19 strain. Resistance to host IRGs was not affected in the Δ rop17 , Δ rop35 , or Δ rop38 / 29 / 19 strain. Collectively, these findings provide the first definitive evidence that the type II T. gondii ROPK proteome functions as virulence factors and facilitates additional mechanisms of host manipulation that are essential for chronic infection and transmission of T. gondii . IMPORTANCE Reactivation of chronic Toxoplasma gondii infection in individuals with weakened immune systems causes severe toxoplasmosis. Existing treatments for toxoplasmosis are complicated by adverse reactions to chemotherapy. Understanding key parasite molecules required for chronic infection provides new insights into potential mechanisms that can interrupt parasite survival or persistence in the host. This study reveals that key secreted rhoptry molecules are used by the parasite to establish chronic infection of the host. Certain rhoptry proteins were found to be critical virulence factors that resist innate immunity, while other rhoptry proteins were found to influence chronic infection without affecting virulence. This study reveals that rhoptry proteins utilize multiple mechanisms of host manipulation to establish chronic infection of the host. Targeted disruption of parasite rhoptry proteins involved in these biological processes opens new avenues to interfere with chronic infection with the goal to either eliminate chronic infection or to prevent recrudescent infections.

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Impact of Engineered Expression of Mitochondrial Association Factor 1b on Toxoplasma gondii Infection and the Host Response in a Mouse Model

mSphere ◽

10.1128/msphere.00471-18 ◽

2018 ◽

Vol 3 (5) ◽

Cited By ~ 2

Author(s):

Elizabeth D. English ◽

Jon P. Boyle

Keyword(s):

Toxoplasma Gondii ◽

Chronic Infection ◽

Acute Infection ◽

Chronic Phase ◽

Parasite Burden ◽

Cytokine Signaling ◽

Parasite Protein ◽

Content Type ◽

Life Threatening ◽

The Impact

ABSTRACT The opportunistic intracellular parasite Toxoplasma gondii causes a lifelong chronic infection capable of reactivating in immunocompromised individuals, which can lead to life-threatening complications. Following invasion of the host cell, host mitochondria associate with the parasitophorous vacuole membrane. This phenotype is T. gondii strain specific and is mediated by expression of a host mitochondrial association-competent (HMA+) paralog of the parasite protein mitochondrial association factor 1 (MAF1b). Previous work demonstrated that expression of MAF1b in strains that do not normally associate with host mitochondria increases their fitness during acute infection in vivo. However, the impact of MAF1b expression during chronic T. gondii infection is unclear. In this study, we assess the impact of MAF1b expression on cyst formation and cytokine production in mice. Despite generally low numbers of cysts generated by the in vitro culture-adapted strains used in this study, we find that parasites expressing MAF1b have higher numbers of cysts in the brains of chronically infected mice and that MAF1b+ cyst burden significantly increases during the course of chronic infection. Consistent with this, mice infected with MAF1b+ parasites have higher levels of the serum cytokines RANTES and VEGF (vascular endothelial growth factor) at day 57 postinfection, although this could be due to higher parasite burden at this time point rather than direct manipulation of these cytokines by MAF1b. Overall these data indicate that MAF1b expression may also be important in determining infection outcome during the chronic phase, either by directly altering the cytokine/signaling environment or by increasing proliferation during the acute and/or chronic phase. IMPORTANCE The parasite Toxoplasma gondii currently infects approximately one-third of the world’s population and causes life-threatening toxoplasmosis in individuals with undeveloped or weakened immune systems. Current treatments are unable to cure T. gondii infection, leaving infected individuals with slow-growing tissue cysts for the remainder of their lives. Previous work has shown that expression of the parasite protein mitochondrial association factor 1 (MAF1b) is responsible for the association of T. gondii parasites with host mitochondria and provides a selective advantage during acute infection. Here we examine the impact of MAF1b expression during chronic T. gondii infection. We find that mice infected with MAF1b-expressing parasites have higher cyst burden and cytokine levels than their wild-type counterparts. A better understanding of the genes involved in establishing and maintaining chronic infection will aid in discovering effective therapeutics for chronically infected individuals.

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Silicon Fertilization Affects Growth of Hybrid Phalaenopsis Orchid Liners

HortTechnology ◽

10.21273/horttech.20.3.603 ◽

2010 ◽

Vol 20 (3) ◽

pp. 603-607 ◽

Cited By ~ 5

Author(s):

Wagner A. Vendrame ◽

Aaron J. Palmateer ◽

Ania Pinares ◽

Kimberly A. Moore ◽

Lawrence E. Datnoff

Keyword(s):

Dry Weight ◽

Long Term Effects ◽

Fresh Weight ◽

Tissue Concentrations ◽

Complete Life Cycle ◽

Silicon Fertilization ◽

Whole Plant ◽

Si Content ◽

Control Water

Experiments were conducted during two different time periods to determine if hybrid phalaenopsis orchid (Phalaenopsis spp.) liners accumulate silicon (Si) and if this element can affect liner growth. A total of 800 liners were evaluated and Si fertilization was performed by applying potassium silicate (KSiO3) as a drench with three treatments (0.5%, 1.0%, and 2.0% v/v) and a control (water, no Si fertilization). The application of KSiO3 affected overall growth of phalaenopsis orchid liners, where Si content of the plant ranged from 0.5% to 1.7%. Overall, Si applied at 0.5% and 1.0% increased fresh weight and dry weight (DW) and at 1.0% Si significantly increased DW of root, shoot, and whole plant over the control. Increases in DW ranged from 27% up to 118%. Results from the second experiment were similar. Other plant parameters evaluated such as leaf number and size, root number, and length were unaffected by Si application. Although leaves of phalaenopsis orchid liners treated with Si appeared darker green when compared with the control, no significant differences were observed in chlorophyll content of leaves. Reduced growth was observed when 2.0% Si was applied affecting Si tissue concentrations and substrate electric conductivity. The data obtained from this study indicate that hybrid phalaenopsis orchid liners are Si accumulators and that this element influences their growth. Further studies are warranted to address the long-term effects of Si fertilization on the complete life cycle of hybrid phalaenopsis orchids.

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Nonreplicating, Cyst-Defective Type II Toxoplasma gondii Vaccine Strains Stimulate Protective Immunity against Acute and Chronic Infection

Infection and Immunity ◽

10.1128/iai.02756-14 ◽

2015 ◽

Vol 83 (5) ◽

pp. 2148-2155 ◽

Cited By ~ 20

Author(s):

Barbara A. Fox ◽

David J. Bzik

Keyword(s):

Toxoplasma Gondii ◽

Chronic Infection ◽

Acute Infection ◽

Cyst Formation ◽

Type I ◽

Type Ii ◽

Live Attenuated Vaccine ◽

Content Type ◽

Monophosphate Decarboxylase ◽

Uracil Auxotroph

Live attenuated vaccine strains, such as type I nonreplicating uracil auxotroph mutants, are highly effective in eliciting lifelong immunity to virulent acute infection byToxoplasma gondii. However, it is currently unknown whether vaccine-elicited immunity can provide protection against acute infection and also prevent chronic infection. To address this problem, we developed nonreverting, nonreplicating, live attenuated uracil auxotroph vaccine strains in the type II Δku80genetic background by targeting the deletion of the orotidine 5′-monophosphate decarboxylase (OMPDC) and uridine phosphorylase (UP) genes. Deletion ofOMPDCinduced a severe uracil auxotrophy with loss of replication, loss of virulence in mice, and loss of the ability to develop cysts and chronic infection. Vaccination of mice using type II Δku80Δompdcmutants stimulated a fully protective CD8+T cell-dependent immunity that prevented acute infection by type I and type II strains ofT. gondii, and this vaccination also severely reduced or prevented cyst formation after type II challenge infection. Nonreverting, nonreplicating, and non-cyst-forming Δompdcmutants provide new tools to examine protective immune responses elicited by vaccination with a live attenuated type II vaccine.

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Zika Virus Causes Acute Infection and Inflammation in the Ovary of Mice Without Apparent Defects in Fertility

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz239 ◽

2019 ◽

Vol 220 (12) ◽

pp. 1904-1914 ◽

Cited By ~ 4

Author(s):

Elizabeth A Caine ◽

Suzanne M Scheaffer ◽

Darcy E Broughton ◽

Vanessa Salazar ◽

Jennifer Govero ◽

...

Keyword(s):

T Cells ◽

Acute Phase ◽

Zika Virus ◽

Acute Infection ◽

Long Term Effects ◽

Zikv Infection ◽

Infection And Inflammation ◽

Global Concern ◽

Follicular Reserve

Abstract Background Zika virus (ZIKV) has become a global concern because infection of pregnant mothers was linked to congenital birth defects. Zika virus is unique from other flaviviruses, because it is transmitted vertically and sexually in addition to by mosquito vectors. Prior studies in mice, nonhuman primates, and humans have shown that ZIKV targets the testis in males, resulting in persistent infection and oligospermia. However, its effects on the corresponding female gonads have not been evaluated. Methods In this study, we assessed the effects of ZIKV on the ovary in nonpregnant mice. Results During the acute phase, ZIKV productively infected the ovary causing accumulation of CD4+ and virus-specific CD8+ T cells. T cells protected against ZIKV infection in the ovary, as higher viral burden was measured in CD8−/− and TCRβδ−/− mice. Increased cell death and tissue inflammation in the ovary was observed during the acute phase of infection, but this normalized over time. Conclusions In contrast to that observed with males, minimal persistence and no long-term consequences of ZIKV infection on ovarian follicular reserve or fertility were demonstrated in this model. Thus, although ZIKV replicates in cells of the ovary and causes acute oophoritis, there is rapid resolution and no long-term effects on fertility, at least in mice.

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IgG AVIDITY WESTERN BLOT USING Toxoplasma gondii rGRA-7 CLONED FROM NUCLEOTIDES 39-711 FOR SERODIAGNOSIS OF ACUTE TOXOPLASMOSIS

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652013000200003 ◽

2013 ◽

Vol 55 (2) ◽

pp. 79-83 ◽

Cited By ~ 5

Author(s):

Poonam S. Deshpande ◽

Dupadahalli Kotresha ◽

Rahmah Noordin ◽

Muhammad Hafiznur Yunus ◽

Geita Saadatnia ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Western Blot ◽

Chronic Infection ◽

Acute Infection ◽

Congenital Infection ◽

Recombinant Antigen ◽

Serum Samples ◽

Serological Profile ◽

Igg Avidity ◽

Acute Toxoplasmosis

Toxoplasmosis is an important cause of congenital infection. The present study was performed to evaluate the usefulness of recombinant (r) GRA-7 cloned from nucleotides (n) 39-711 in discriminating between acute and chronic toxoplasmosis. First, commercial IgM, IgG and IgG avidity ELISAs were used to determine the serological profile of the sera. Serum samples were from 20 symptomatic patients with acute infection (low IgG avidity, IgM positive), 10 with chronic infection (high IgG avidity, IgM negative) and 10 with indeterminate IgG avidity (IgM positive) which were tested for IgG avidity status with an in-house developed IgG avidity Western blot using the rGRA-7 recombinant antigen. All 20 sera from cases of probable acute infection showed bands which either faded out completely or reduced significantly in intensity after treatment with 8 M urea, whereas the band intensities of the 10 serum samples from chronic cases remained the same. Of the 10 sera with indeterminate IgG avidity status, after treatment with 8 M urea the band intensities with six sera remained the same, two sera had completely faded bands and another two sera had significantly reduced band intensities. Discrimination between acute and chronic toxoplasmosis was successfully performed by the in-house IgG avidity Western blot.

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Long-Term Relationships: the Complicated Interplay between the Host and the Developmental Stages of Toxoplasma gondii during Acute and Chronic Infections

Microbiology and Molecular Biology Reviews ◽

10.1128/mmbr.00027-15 ◽

2015 ◽

Vol 79 (4) ◽

pp. 387-401 ◽

Cited By ~ 40

Author(s):

Kelly J. Pittman ◽

Laura J. Knoll

Keyword(s):

Toxoplasma Gondii ◽

Chronic Infection ◽

Developmental Stages ◽

Acute Infection ◽

The Body ◽

Sexual Cycle ◽

Parasitic Infections ◽

Chronic Infections ◽

Content Type ◽

Cyst Form

SUMMARYToxoplasma gondiirepresents one of the most common parasitic infections in the world. The asexual cycle can occur within any warm-blooded animal, but the sexual cycle is restricted to the feline intestinal epithelium.T. gondiiis acquired through consumption of tissue cysts in undercooked meat as well as food and water contaminated with oocysts. Once ingested, it differentiates into a rapidly replicating asexual form and disseminates throughout the body during acute infection. After stimulation of the host immune response,T. gondiidifferentiates into a slow-growing, asexual cyst form that is the hallmark of chronic infection. One-third of the human population is chronically infected withT. gondiicysts, which can reactivate and are especially dangerous to individuals with reduced immune surveillance. Serious complications can also occur in healthy individuals if infected with certainT. gondiistrains or if infection is acquired congenitally. No drugs are available to clear the cyst form during the chronic stages of infection. This therapeutic gap is due in part to an incomplete understanding of both host and pathogen responses during the progression ofT. gondiiinfection. While many individual aspects ofT. gondiiinfection are well understood, viewing the interconnections between host and parasite during acute and chronic infection may lead to better approaches for future treatment. The aim of this review is to provide an overview of what is known and unknown about the complex relationship between the host and parasite during the progression ofT. gondiiinfection, with the ultimate goal of bridging these events.

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Functional Analysis of the Rhoptry Kinome during ChronicToxoplasma gondiiInfection

mBio ◽

10.1128/mbio.00842-16 ◽

2016 ◽

Vol 7 (3) ◽

Cited By ~ 4

Author(s):

Laura J. Knoll

Keyword(s):

Functional Analysis ◽

Toxoplasma Gondii ◽

Chronic Infection ◽

Drug Targets ◽

Acute Infection ◽

Deletion Analysis ◽

Parasitic Infections ◽

Link Type ◽

Novel Drug ◽

Novel Drug Targets

ABSTRACTToxoplasma gondiiis one of the most common parasitic infections of humans worldwide. Once exposed, humans remain infected withT. gondiifor life, and there are no therapeutics capable of eliminating a chronic infection. In the search for novel drug targets,T. gondiiis known to contain several unique secretory organelles, one of which is called the rhoptries. Rhoptry organelles contain and secrete numerous proteins with kinase domains, but the roles of most of these kinases during infection remain unknown. In a recent mBio article, B. A. Fox et al. [mBio 7(3):e00193-16, 2016,http://dx.doi.org/10.1128/mBio.00193-16] performed a tour de force deletion analysis of 31 rhoptry kinases and examined their roles in the development of chronic infection. While rhoptry kinase deletion strains that displayed an acute infection defect also showed a reduction in chronic infection cyst burden, two rhoptry kinase deletion strains had decreased cyst burden without any change in acute virulence. These results indicate the necessity of the rhoptry kinases for the establishment and perhaps maintenance of chronic infection. They also highlight the potential of these kinases as drug targets to clear chronic infection or as candidates to generate a nonpersisting vaccine.

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