Parasite Replication and the Evolutionary Epidemiology of Parasite Virulence

AbstractCytoskeletal structures of Apicomplexan parasites are important for parasite replication, motility, invasion to the host cell and survival. Apicortin, an Apicomplexan specific protein appears to be a crucial factor in maintaining stability of the parasite cytoskeletal assemblies. However, the function of apicortin, in terms of interaction with microtubules still remains elusive. Herein, we have attempted to elucidate the function of Plasmodium falciparum apicortin by monitoring its interaction with two main components of parasite microtubular structure, α-tubulin-I and β-tubulin through in silico and in vitro studies. Further, a p25 domain binding generic drug Tamoxifen (TMX), was used to disrupt PfApicortin-tubulin interactions which led to the inhibition in growth and progression of blood stage life cycle of P. falciparum.

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Loss of the Conserved Alveolate Kinase MAPK2 Decouples Toxoplasma Cell Growth from Cell Division

mBio ◽

10.1128/mbio.02517-20 ◽

2020 ◽

Vol 11 (6) ◽

Author(s):

Xiaoyu Hu ◽

William J. O’Shaughnessy ◽

Tsebaot G. Beraki ◽

Michael L. Reese

Keyword(s):

Toxoplasma Gondii ◽

Protein Kinases ◽

Daughter Cell ◽

Protozoan Parasite ◽

Productive Infection ◽

Centrosome Duplication ◽

Loss Of Function ◽

Content Type ◽

Mitogen Activated Protein ◽

Parasite Replication

ABSTRACT Mitogen-activated protein kinases (MAPKs) are a conserved family of protein kinases that regulate signal transduction, proliferation, and development throughout eukaryotes. The apicomplexan parasite Toxoplasma gondii expresses three MAPKs. Two of these, extracellular signal-regulated kinase 7 (ERK7) and MAPKL1, have been implicated in the regulation of conoid biogenesis and centrosome duplication, respectively. The third kinase, MAPK2, is specific to and conserved throughout the Alveolata, although its function is unknown. We used the auxin-inducible degron system to determine phenotypes associated with MAPK2 loss of function in Toxoplasma. We observed that parasites lacking MAPK2 failed to duplicate their centrosomes and therefore did not initiate daughter cell budding, which ultimately led to parasite death. MAPK2-deficient parasites initiated but did not complete DNA replication and arrested prior to mitosis. Surprisingly, the parasites continued to grow and replicate their Golgi apparatus, mitochondria, and apicoplasts. We found that the failure in centrosome duplication is distinct from the phenotype caused by the depletion of MAPKL1. As we did not observe MAPK2 localization at the centrosome at any point in the cell cycle, our data suggest that MAPK2 regulates a process at a distal site that is required for the completion of centrosome duplication and the initiation of parasite mitosis. IMPORTANCE Toxoplasma gondii is a ubiquitous intracellular protozoan parasite that can cause severe and fatal disease in immunocompromised patients and the developing fetus. Rapid parasite replication is critical for establishing a productive infection. Here, we demonstrate that a Toxoplasma protein kinase called MAPK2 is conserved throughout the Alveolata and essential for parasite replication. We found that parasites lacking MAPK2 protein were defective in the initiation of daughter cell budding and were rendered inviable. Specifically, T. gondii MAPK2 (TgMAPK2) appears to be required for centrosome replication at the basal end of the nucleus, and its loss causes arrest early in parasite division. MAPK2 is unique to the Alveolata and not found in metazoa and likely is a critical component of an essential parasite-specific signaling network.

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Population genomic datasets describing the post-vaccine evolutionary epidemiology of Streptococcus pneumoniae

Scientific Data ◽

10.1038/sdata.2015.58 ◽

2015 ◽

Vol 2 (1) ◽

Cited By ~ 31

Author(s):

Nicholas J. Croucher ◽

Jonathan A. Finkelstein ◽

Stephen I. Pelton ◽

Julian Parkhill ◽

Stephen D. Bentley ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Population Genomic ◽

Evolutionary Epidemiology

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Benznidazole Treatment following Acute Trypanosoma cruzi Infection Triggers CD8+ T-Cell Expansion and Promotes Resistance to Reinfection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.12.3790-3796.2002 ◽

2002 ◽

Vol 46 (12) ◽

pp. 3790-3796 ◽

Cited By ~ 25

Author(s):

Bianca Perdigão Olivieri ◽

Vinícius Cotta-de-Almeida ◽

Tania Araújo-Jorge

Keyword(s):

T Lymphocytes ◽

Trypanosoma Cruzi ◽

Immune Regulation ◽

Immune Dysregulation ◽

Direct Role ◽

Parasite Replication ◽

The Impact ◽

Shed Light ◽

Cruzi Infection

ABSTRACT Many studies have shed light on the mechanisms underlying both immunoprotection and immune dysregulation arising after Trypanosoma cruzi infection. However, little is known about the impact of benznidazole (N-benzyl-2-nitroimidazole acetamide), the drug available for clinical treatment of the infection, on the immune system in the infected host. In the present study we investigated the effect of benznidazole therapy on the lymphoid compartment during the course of experimental T. cruzi infection. Although amelioration of a variety of clinical and parasitological signs was observed in treated mice, amelioration of splenocyte expansion was not detected. Interestingly, this sustained splenomegaly observed in benznidazole-treated mice showed a preferential expansion of CD8+ T lymphocytes. Moreover, although benznidazole treatment blocked the expansion of recently activated CD4+ and CD8+ T cells seen in infected hosts, benznidazole treatment led to a selective expansion of effector and memory CD8+ T lymphocytes in association with a lower rate of apoptosis. In addition, the surviving treated animals were protected from reinfection. Together, these data suggest that, in addition to its well-known direct role in blocking parasite replication in vivo, benznidazole appears to directly affect immune regulation in T. cruzi-infected hosts.

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Microtubules, but not actin filaments, drive daughter cell budding and cell division in Toxoplasma gondii

Journal of Cell Science ◽

10.1242/jcs.113.7.1241 ◽

2000 ◽

Vol 113 (7) ◽

pp. 1241-1254 ◽

Cited By ~ 1

Author(s):

M.K. Shaw ◽

H.L. Compton ◽

D.S. Roos ◽

L.G. Tilney

Keyword(s):

Toxoplasma Gondii ◽

Actin Cytoskeleton ◽

Daughter Cell ◽

Protozoan Parasite ◽

Host Cells ◽

Actin Dynamics ◽

Residual Body ◽

Cell Organelles ◽

Infection Period ◽

Parasite Replication

We have used drugs to examine the role(s) of the actin and microtubule cytoskeletons in the intracellular growth and replication of the intracellular protozoan parasite, Toxoplasma gondii. By using a 5 minute infection period and adding the drugs shortly after entry we can treat parasites at the start of intracellular development and 6–8 hours prior to the onset of daughter cell budding. Using this approach we found, somewhat surprisingly, that reagents that perturb the actin cytoskeleton in different ways (cytochalasin D, latrunculin A and jasplakinolide) had little effect on parasite replication although they had the expected effects on the host cells. These actin inhibitors did, however, disrupt the orderly turnover of the mother cell organelles leading to the formation of a large residual body at the posterior end of each pair of budding parasites. Treating established parasite cultures with the actin inhibitors blocked ionophore-induced egression of tachyzoites from the host cells, demonstrating that intracellular parasites were susceptible to the effects of these inhibitors. In contrast, the anti-microtubule drugs oryzalin and taxol, and to a much lesser extent nocodazole, which affect microtubule dynamics in different ways, blocked parasite replication by disrupting the normal assembly of the apical conoid and the microtubule inner membrane complex (IMC) in the budding daughter parasites. Centrosome replication and assembly of intranuclear spindles, however, occurred normally. Thus, daughter cell budding per se is dependent primarily on the parasite microtubule system and does not require a dynamic actin cytoskeleton, although disruption of actin dynamics causes problems in the turnover of parasite organelles.

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Invasion of mature and immature erythrocytes of CBA/Ca mice by a cloned line of Plasmodium chabaudi chabaudi

Parasitology ◽

10.1017/s0031182000058583 ◽

1989 ◽

Vol 99 (2) ◽

pp. 157-163 ◽

Cited By ~ 22

Author(s):

W. Jarra ◽

K. N. Brown

Keyword(s):

No Reduction ◽

Plasmodium Chabaudi ◽

Equal Frequency ◽

Early Stages ◽

Parasite Replication ◽

Parasite Populations ◽

Peak Parasitaemia

SummaryDuring the early stages of the primary Plasmodium chabaudi chabaudi AS parasitaemia in CBA/Ca mice this parasite invaded normocytes, but as the parasitaemia developed increasing numbers of parasites were seen within reticulocytes. During and just after peak parasitaemia, as further parasite replication was controlled, the ‘crisis’ phase ensued, mice became increasingly anaemic and reticulocyte numbers were markedly increased. As the parasitaemia was resolved during crisis in excess of 25% of parasites had invaded reticulocytes. In phenylhydrazine-pretreated mice with artificially high reticulocyte levels and infected with P. c. chabaudi AS, normocyte/reticulocyte invasion occurred with equal frequency. No reduction in the infectivity of parasite populations developing in reticulocytes was observed.

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Host-Directed Therapies for Cutaneous Leishmaniasis

Frontiers in Immunology ◽

10.3389/fimmu.2021.660183 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fernanda O. Novais ◽

Camila Farias Amorim ◽

Phillip Scott

Keyword(s):

Cutaneous Leishmaniasis ◽

Inflammatory Diseases ◽

Wide Spectrum ◽

Substantial Evidence ◽

Novel Approach ◽

Clinical Presentations ◽

Wide Range ◽

Parasite Replication ◽

Inflammatory Drugs ◽

Improve Clinical Outcome

Cutaneous leishmaniasis exhibits a wide spectrum of clinical presentations from self-resolving infections to severe chronic disease. Anti-parasitic drugs are often ineffective in the most severe forms of the disease, and in some cases the magnitude of the disease can result from an uncontrolled inflammatory response rather than unrestrained parasite replication. In these patients, host-directed therapies offer a novel approach to improve clinical outcome. Importantly, there are many anti-inflammatory drugs with known safety and efficacy profiles that are currently used for other inflammatory diseases and are readily available to be used for leishmaniasis. However, since leishmaniasis consists of a wide range of clinical entities, mediated by a diverse group of leishmanial species, host-directed therapies will need to be tailored for specific types of leishmaniasis. There is now substantial evidence that host-directed therapies are likely to be beneficial beyond autoimmune diseases and cancer and thus should be an important component in the armamentarium to modulate the severity of cutaneous leishmaniasis.

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Leishmania Specific CD4 T Cells Release IFNγ That Limits Parasite Replication in Patients with Visceral Leishmaniasis

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0003198 ◽

2014 ◽

Vol 8 (10) ◽

pp. e3198 ◽

Cited By ~ 40

Author(s):

Rajiv Kumar ◽

Neetu Singh ◽

Shalini Gautam ◽

Om Prakash Singh ◽

Kamlesh Gidwani ◽

...

Keyword(s):

T Cells ◽

Visceral Leishmaniasis ◽

Cd4 T Cells ◽

Parasite Replication

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Global emergence and evolutionary dynamics of bluetongue virus

Scientific Reports ◽

10.1038/s41598-020-78673-9 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Moh A. Alkhamis ◽

Cecilia Aguilar-Vega ◽

Nicholas M. Fountain-Jones ◽

Kai Lin ◽

Andres M. Perez ◽

...

Keyword(s):

Bluetongue Virus ◽

Evolutionary Dynamics ◽

Transmission Dynamics ◽

Intervention Programs ◽

Economic Losses ◽

Molecular Surveillance ◽

China And India ◽

Evolutionary Epidemiology ◽

Livestock Trade

AbstractBluetongue virus (BTV) epidemics are responsible for worldwide economic losses of up to US$ 3 billion. Understanding the global evolutionary epidemiology of BTV is critical in designing intervention programs. Here we employed phylodynamic models to quantify the evolutionary characteristics, spatiotemporal origins, and multi-host transmission dynamics of BTV across the globe. We inferred that goats are the ancestral hosts for BTV but are less likely to be important for cross-species transmission, sheep and cattle continue to be important for the transmission and maintenance of infection between other species. Our models pointed to China and India, countries with the highest population of goats, as the likely ancestral country for BTV emergence and dispersal worldwide over 1000 years ago. However, the increased diversification and dispersal of BTV coincided with the initiation of transcontinental livestock trade after the 1850s. Our analysis uncovered important epidemiological aspects of BTV that may guide future molecular surveillance of BTV.

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