Neospora caninum in non-pregnant and pregnant mouse models: cross-talk between infection and immunity

doi:10.1016/j.ijpara.2017.09.001

International Journal for Parasitology

Volume 47, Issue 12, October 2017, Pages 723-735

https://doi.org/10.1016/j.ijpara.2017.09.001 Get rights and content

Highlights

•
Mouse models have been used widely for studies on the immunology of neosporosis.
•
Mouse models are very useful in defining hallmarks of the immune response to Neospora caninum.
•
The innate immune system plays an important role in the initiation of the immune response.
•
IFNγ and the Th1 response are essential for controlling N. caninum acute infection in non-pregnant mice.
•
Pregnancy-associated immunomodulation interferes with the immune response to N. caninum and needs to be clarified.

Abstract

Neospora caninum is a cyst-forming coccidian which causes abortion in cattle, with a high economic impact globally. Vaccination is considered to be the most cost-effective strategy to control and prevent bovine neosporosis. However, there is no commercial vaccine available to date. To investigate this disease under laboratory conditions, mouse models were developed, and they have been efficiently used as an initial proof-of-concept platform to investigate different immunogenic formulations. We here provide a detailed review on the current knowledge on immunity against neosporosis in non-pregnant as well as pregnant mice, and present a general overview of the most relevant parameters that may be responsible for protective immunity, which in turn could be relevant for vaccine development. Despite the considerable differences in immunity between cattle and mice, it is essential to understand how mice respond immunologically to Neospora caninum infection and how this response influences congenital infection and offspring survival. In this context, pregnant mouse models play a key role, and allow correlation of the outcome of congenital neosporosis with specific immune mechanisms which could also be relevant in cattle.

Graphical abstract

Introduction

Neospora caninum is an apicomplexan parasite closely related to Toxoplasma gondii that infects canids as definitive hosts and cattle as the intermediate hosts of primary economic concern. Neosporosis is one of the most important infectious causes of abortion in cattle worldwide and based on data from 10 countries, the annual financial losses were calculated to range from US $1.1 million in the New Zealand beef industry to US $546.3 million in the US dairy population (Reichel et al., 2013). The only marketed vaccine, Neoguard™, has been removed due to ambiguous efficacy, and currently there is neither a vaccine nor a drug commercially available for the prevention and treatment of bovine neosporosis. Considering that reproductive losses represent the main economic burden of this disease and that vertical transmission has an important role in maintaining the parasite in cattle herds (Dubey et al., 2017), future vaccines should ideally be able not only to protect against primary infection by oocysts but also be safe during gestation and reduce, if not eliminate, vertical transmission.

To approach vaccine development against N. caninum infection rationally, it is important to gain knowledge on the hallmarks of the immunological response against infection, and to define the crucial parameters that determine whether the host can eliminate the invading pathogen or whether the disease is induced. Whilst such investigations should be ideally carried out in cattle as the main host of economic interest, only a few laboratories worldwide have the capacity to do this, and respective studies have been recently reviewed (Horcajo et al., 2016). The majority of investigations on immunity against neosporosis have been carried out in small laboratory animal models such as mice, with extraordinary advantages in terms of the required facilities, costs, time and availability of tools to dissect the immune response. Non-pregnant as well as pregnant mouse models have proven to be useful and versatile for studies on host-parasite interactions, immunity, vaccination trials and novel therapeutic approaches against neosporosis (Hemphill et al., 2016, Dubey et al., 2017). In addition, experimental investigations on neosporosis in mice allow us to draw analogies to similar studies on the closely related T. gondii, whose interactions with the murine host are better characterised, and could potentially serve as an inspiration for the design of novel experiments and trouble-shooting to shed more light on how host immunity deals with N. caninum infection.

We here provide a review of the last 20 years of research on immunity against experimental neosporosis in mice, by covering the major hallmarks of the immune response in both non-pregnant and pregnant mouse models during infection. We also explore the correlation of these immune parameters with protection against infection and disease, and we refer to studies that have aimed to show how the cross-talk between innate and acquired immunity could be exploited for future vaccine development.

Section snippets

Immune response to N. caninum infection in non-pregnant mice

Experimental N. caninum infection has been mostly induced by cell culture-derived tachyzoites, mainly through s.c. or i.p. inoculation (Long et al., 1998, Collantes-Fernandez et al., 2004, Collantes-Fernandez et al., 2006a, Pereira Garcia-Melo et al., 2010) and, in some instances, by intragastric inoculation (Correia et al., 2013, Teixeira et al., 2015). During the acute phase of the experimental infection, the parasites proliferate in several organs of the mouse but the burden diminishes

Consequences of infection for pregnancy and the progeny

Primary N. caninum infection of mice between days 6–9 of pregnancy has fatal consequences for the progeny, which develop a progressive syndrome characterised by a rapid neurological disease and development impairment, leading to necrotizing encephalitis and hepatitis, and death within 3 or 4 weeks after birth (Lopez-Perez et al., 2008, Arranz-Solis et al., 2015). Placental invasion induces a strong local inflammation leading to hypoxia and foetal damage. However, pathology can also be caused by

Where to go from here

Since the discovery of N. caninum, mice have been consistently used for experimental studies on the immunology of neosporosis, although there are obvious differences between ruminants and mice with regard to their immunological properties. Nevertheless, experimental infections in mice have been highly useful in defining several hallmarks of the immune response against this parasite, and the murine model has offered the possibility to work with defined genetically depleted animals and

Acknowledgements

The authors acknowledge the financial support of the Swiss National Science Foundation, Switzerland (grants No. 310030_146162 and 310030_165782) and Fundação para a Ciência e a Tecnologia, Portugal (grant No. PTDC/CVT/1133889/2009). We thank all authors cited in this review and apologize to those also contributing to the knowledge of T. gondii and N. caninum-associated immunity but not described here due to space limitations.

References (106)

A. Aguado-Martinez et al.
Failure of a vaccine using immunogenic recombinant proteins rNcSAG4 and rNcGRA7 against neosporosis in mice
Vaccine
(2009)
D. Arranz-Solis et al.
Dose-dependent effects of experimental infection with the virulent Neospora caninum Nc-Spain7 isolate in a pregnant mouse model
Vet. Parasitol.
(2015)
A.S. Botelho et al.
Neospora caninum: high susceptibility to the parasite in C57BL/10ScCr mice
Exp. Parasitol.
(2007)
D.A. Brake
Vaccinology for control of apicomplexan parasites: a simplified language of immune programming and its use in vaccine design
Int. J. Parasitol.
(2002)
M.R. Cardoso et al.
ArtinM, a D-mannose-binding lectin from Artocarpus integrifolia, plays a potent adjuvant and immunostimulatory role in immunization against Neospora caninum
Vaccine
(2011)
E. Collantes-Fernandez et al.
Influence of the stage of pregnancy on Neospora caninum distribution, parasite loads and lesions in aborted bovine foetuses
Theriogenology
(2006)
K. Debache et al.
Vaccination with recombinant NcROP2 combined with recombinant NcMIC1 and NcMIC3 reduces cerebral infection and vertical transmission in mice experimentally infected with Neospora caninum tachyzoites
Int. J. Parasitol.
(2009)
K. Debache et al.
Vaccination of mice with recombinant NcROP2 antigen reduces mortality and cerebral infection in mice infected with Neospora caninum tachyzoites
Int. J. Parasitol.
(2008)
S. Dion et al.
Functional activation of T cells by dendritic cells and macrophages exposed to the intracellular parasite Neospora caninum
Int. J. Parasitol.
(2011)
M. Ghaebi et al.
Immune regulatory network in successful pregnancy and reproductive failures
Biomed. Pharmacother.
(2017)

G.J. Haldorson et al.

Immunization with native surface protein NcSRS2 induces a Th2 immune response and reduces congenital Neospora caninum transmission in mice

Int. J. Parasitol.

(2005)

M.C. Jenkins et al.

Neospora caninum: cloning and expression of a gene coding for cytokine-inducing profilin

Exp. Parasitol.

(2010)

E. Jimenez-Ruiz et al.

Mice congenitally infected with low-to-moderate virulence Neospora caninum isolates exhibited clinical reactivation during the mating period without transmission to the next generation

Exp. Parasitol.

(2013)

R. Kano et al.

Relationship between type 1/type 2 immune responses and occurrence of vertical transmission in BALB/c mice infected with Neospora caninum

Vet. Parasitol.

(2005)

I.A. Khan et al.

Neospora caninum: role for immune cytokines in host immunity

Exp. Parasitol.

(1997)

S. Klevar et al.

Natural killer cells act as early responders in an experimental infection with Neospora caninum in calves

Int. J. Parasitol.

(2007)

I.C. Lopez-Perez et al.

Influence of Neospora caninum infection in BALB/c mice during pregnancy in post-natal development

Vet. Parasitol.

(2008)

A. Lunden et al.

Immunisation of mice against neosporosis

Int. J. Parasitol.

(2002)

F.C. Mansilla et al.

Immunization with Neospora caninum profilin induces limited protection and a regulatory T-cell response in mice

Exp. Parasitol.

(2016)

M.L. Mazuz et al.

Neospora caninum: Chronic and congenital infection in consecutive pregnancies of mice

Vet. Parasitol.

(2016)

T. Monney et al.

Vaccination with the recombinant chimeric antigen recNcMIC3-1-R induces a non-protective Th2-type immune response in the pregnant mouse model for N. caninum infection

Vaccine

(2012)

T. Monney et al.

Vaccines against neosporosis: what can we learn from the past studies?

Exp. Parasitol.

(2014)

T. Monney et al.

RecNcMIC3-1-R is a microneme- and rhoptry-based chimeric antigen that protects against acute neosporosis and limits cerebral parasite load in the mouse model for Neospora caninum infection

Vaccine

(2011)

I. Pastor-Fernandez et al.

A vaccine formulation combining rhoptry proteins NcROP40 and NcROP2 improves pup survival in a pregnant mouse model of neosporosis

Vet. Parasitol.

(2015)

H.E. Quinn et al.

The cell-mediated immune response to Neospora caninum during pregnancy in the mouse is associated with a bias towards production of interleukin-4

Int. J. Parasitol.

(2004)

S. Ramamoorthy et al.

Prevention of lethal experimental infection of C57BL/6 mice by vaccination with Brucella abortus strain RB51 expressing Neospora caninum antigens

Int. J. Parasitol.

(2007)

J. Regidor-Cerrillo et al.

Neospora caninum tachyzoite immunome study reveals differences among three biologically different isolates

Vet. Parasitol.

(2015)

M.P. Reichel et al.

What is the global economic impact of Neospora caninum in cattle - the billion dollar question

Int. J. Parasitol.

(2013)

D.P. Ribeiro et al.

CpG-ODN combined with Neospora caninum lysate, but not with excreted-secreted antigen, enhances protection against infection in mice

Vaccine

(2009)

S. Rojo-Montejo et al.

Influence of adjuvant and antigen dose on protection induced by an inactivated whole vaccine against Neospora caninum infection in mice

Vet. Parasitol.

(2011)

A. Senegas et al.

Toxoplasma gondii-induced foetal resorption in mice involves interferon-gamma-induced apoptosis and spiral artery dilation at the maternofoetal interface

Int. J. Parasitol.

(2009)

J.A. Spencer et al.

Neospora caninum: adoptive transfer of immune lymphocytes precipitates disease in BALB/c mice

Vet. Immunol. Immunopathol.

(2005)

T. Tanaka et al.

The role of CD4(+) or CD8(+) T cells in the protective immune response of BALB/c mice to Neospora caninum infection

Vet. Parasitol.

(2000)

C. Abe et al.

Role of the chemokine receptor CCR5-dependent host defense system in Neospora caninum infections

Parasite Vectors

(2015)

A. Abou-Bacar et al.

Role of NK cells and gamma interferon in transplacental passage of Toxoplasma gondii in a mouse model of primary infection

Infect. Immun.

(2004)

A. Abou-Bacar et al.

Role of gamma interferon and T cells in congenital Toxoplasma transmission

Parasite Immunol.

(2004)

A. Aguado-Martínez et al.

Characterisation of NcGRA7 and NcSAG4 proteins: immunolocalisation and their role in the host cell invasion by Neospora caninum tachyzoites

Acta Parasitol.

(2010)

A. Aguado-Martinez et al.

N-terminal fusion of a toll-like receptor 2-ligand to a Neospora caninum chimeric antigen efficiently modifies the properties of the specific immune response

Parasitology

(2016)

P.M. Bartley et al.

The development of immune responses in Balb/c mice following inoculation with attenuated or virulent Neospora caninum tachyzoites

Parasite Immunol.

(2009)

T.V. Baszler et al.

Immunization of BALB/c mice with killed Neospora caninum tachyzoite antigen induces a type 2 immune response and exacerbates encephalitis and neurological disease

Clin. Diag. Lab. Immunol.

(2000)

D.P. Beiting et al.

Differential induction of TLR3-dependent innate immune signaling by closely related parasite species

PLoS One

(2014)

P. Boysen et al.

The protozoan Neospora caninum directly triggers bovine NK cells to produce gamma interferon and to kill infected fibroblasts

Infect. Immun.

(2006)

A. Cannas et al.

Vaccination of mice against experimental Neospora caninum infection using NcSAG1- and NcSRS2-based recombinant antigens and DNA vaccines

Parasitology

(2003)

M.R. Cardoso et al.

Adjuvant and immunostimulatory effects of a D-galactose-binding lectin from Synadenium carinatum latex (ScLL) in the mouse model of vaccination against neosporosis

Vet. Res.

(2012)

E. Collantes-Fernandez et al.

Characterization of pathology and parasite load in outbred and inbred mouse models of chronic Neospora caninum infection

J. Parasitol.

(2004)

E. Collantes-Fernandez et al.

Infected dendritic cells facilitate systemic dissemination and transplacental passage of the obligate intracellular parasite Neospora caninum in mice

PLoS One

(2012)

E. Collantes-Fernandez et al.

Temporal distribution and parasite load kinetics in blood and tissues during Neospora caninum infection in mice

Infect. Immun.

(2006)

A. Correia et al.

Predominant role of interferon-gamma in the host protective effect of CD8(+) T cells against Neospora caninum infection

Sci. Rep.

(2015)

A. Correia et al.

Mucosal and systemic T cell response in mice intragastrically infected with Neospora caninum tachyzoites

Vet. Res.

(2013)

M. Davoli-Ferreira et al.

Nucleotide-binding oligomerization domain-containing protein 2 prompts potent inflammatory stimuli during Neospora caninum infection

Sci. Rep.

(2016)

Cited by (39)

Working towards the development of vaccines and chemotherapeutics against neosporosis—With all of its ups and downs—Looking ahead
2024, Advances in Parasitology
Neospora caninum is an apicomplexan and obligatory intracellular parasite, which is the leading cause of reproductive failure in cattle and affects other farm and domestic animals, but also induces neuromuscular disease in dogs of all ages. In cattle, neosporosis is an important health problem, and has a considerable economic impact. To date there is no protective vaccine or chemotherapeutic treatment on the market. Immuno-prophylaxis has long been considered as the best control measure. Proteins involved in host cell interaction and invasion, as well as antigens mediating inflammatory responses have been the most frequently assessed vaccine targets. However, despite considerable efforts no effective vaccine has been introduced to the market to date. The development of effective compounds to limit the effects of vertical transmission of N. caninum tachyzoites has emerged as an alternative or addition to vaccination, provided suitable targets and safe and efficacious drugs can be identified. Additionally, the combination of both treatment strategies might be interesting to further increase protectivity against N. caninum infections and to decrease the duration of treatment and the risk of potential drug resistance. Well-established and standardized animal infection models are key factors for the evaluation of promising vaccine and compound candidates. The vast majority of experimental animal experiments concerning neosporosis have been performed in mice, although in recent years the numbers of experimental studies in cattle and sheep have increased. In this review, we discuss the recent findings concerning the progress in drug and vaccine development against N. caninum infections in mice and ruminants.
Transcriptome profiling of Madin-Darby bovine kidney cells uncover differences in the susceptibility of cattle to Toxoplasma gondii and Neospora caninum
2023, Veterinary Parasitology
Toxoplasma gondii and Neospora caninum are two major apicomplexan protozoan parasites with heteroxenous life cycles and worldwide distributions. The transplacental transmission of N. caninum causes bovine abortion, which resulting in serious economic losses to the dairy industry. Although T. gondii was also reported to cause abortions in pregnant woman and small ruminants, scarce cases about the symptom to the host cattle and the causality remains unknown. In this study, transcriptome analysis of Madin Darby bovine kidney (MDBK) cells infected with T. gondii and N. caninum was performed to uncover the differences in susceptibility of cattle to the two parasites. The results showed that 256 and 2225 differentially expressed genes (DEGs) were detected in cells infected with N. caninum and T. gondii, respectively. Moreover, significant biological differences were revealed by the functional analysis including GO and KEGG enrichment. One serpin peptidase inhibitor (SEPRINA14), which is associated with immunosuppression during pregnancy, was found to significantly decrease in cells infected with N. caninum and increase in cells infected with T. gondii-infected cells. Pattern recognition receptors TLR3 and NOD2 were also significantly upregulated in N. caninum-infected MDBK cells, but not in T. gondii. They could induce an increased inflammatory response leading to severe tissue damage. In addition, the interleukin 12 receptor subunit beta 2 (IL12β2), which plays an essential role in Th1 and Th2 cell differentiation and inflammatory bowel disease, was also markedly upregulated in the N. caninum infected cells, which led to an imbalance in the Th1 and Th2 cells by promoting the Th1 cellular response. Altogether, our findings recognized a new understanding on the differences between T. gondii and N. caninum infection of MDBK cells, where SEPRINA14, TLR3, NOD2, and IL12β2 may be the key genes that affect the difference in susceptibility of cattle to T. gondii and N. caninum, especially in pregnant animals. This study provides more clues as to why N. caninum is more likely to cause abortions in cattle.
Endochin-like quinolones (ELQs) and bumped kinase inhibitors (BKIs): Synergistic and additive effects of combined treatments against Neospora caninum infection in vitro and in vivo
2021, International Journal for Parasitology: Drugs and Drug Resistance
The apicomplexan parasite Neospora caninum is an important causative agent of congenital neosporosis, resulting in abortion, birth of weak offspring and neuromuscular disorders in cattle, sheep, and many other species. Among several compound classes that are currently being developed, two have been reported to limit the effects of congenital neosporosis: (i) bumped kinase inhibitors (BKIs) target calcium dependent protein kinase 1 (CDPK1), an enzyme that is encoded by an apicoplast-derived gene and found only in apicomplexans and plants. CDPK1 is essential for host cell invasion and egress; (ii) endochin-like quinolones (ELQs) are inhibitors of the cytochrome bc₁ complex of the mitochondrial electron transport chain and thus inhibit oxidative phosphorylation. We here report on the in vitro and in vivo activities of BKI-1748, and of ELQ-316 and its respective prodrugs ELQ-334 and ELQ-422, applied either as single-compounds or ELQ-BKI-combinations. In vitro, BKI-1748 and ELQ-316, as well as BKI-1748 and ELQ-334, acted synergistically, while this was not observed for the BKI-1748/ELQ-422 combination treatment. In a N. caninum-infected pregnant BALB/c mouse model, the synergistic effects observed in vitro were not entirely reproduced, but 100% postnatal survival and 100% inhibition of vertical transmission was noted in the group treated with the BKI-1748/ELQ-334 combination. In addition, the combined drug applications resulted in lower neonatal mortality compared to treatments with single drugs.
In vitro activity, safety and in vivo efficacy of the novel bumped kinase inhibitor BKI-1748 in non-pregnant and pregnant mice experimentally infected with Neospora caninum tachyzoites and Toxoplasma gondii oocysts
2021, International Journal for Parasitology: Drugs and Drug Resistance
Bumped kinase inhibitors (BKIs) target the apicomplexan calcium-dependent protein kinase 1 (CDPK1). BKI-1748, a 5-aminopyrazole-4-carboxamide compound when added to fibroblast cells concomitantly to the time of infection, inhibited proliferation of apicomplexan parasites at EC₅₀s of 165 nM (Neospora caninum) and 43 nM (Toxoplasma gondii). Immunofluorescence and electron microscopy showed that addition of 2.5 μM BKI-1748 to infected HFF monolayers transformed parasites into multinucleated schizont-like complexes (MNCs) containing newly formed zoites, which were unable to separate and form infective tachyzoites or undergo egress. In zebrafish (Danio rerio) embryo development assays, no embryonic impairment was detected within 96 h at BKI-1748 concentrations up to 10 μM. In pregnant mice, BKI-1748 applied at days 9–13 of pregnancy at a dose of 20 mg/kg/day was safe and no pregnancy interference was observed. The efficacy of BKI-1748 was assessed in standardized pregnant mouse models infected with N. caninum (NcSpain-7) tachyzoites or T. gondii (TgShSp1) oocysts. In both models, treatments resulted in increased pup survival and profound inhibition of vertical transmission. However, in dams and non-pregnant mice, BKI-1748 treatments resulted in significantly decreased cerebral parasite loads only in T. gondii infected mice. In the T. gondii-model, ocular infection was detected in 10 out of 12 adult mice of the control group, but only in 3 out of 12 mice in the BKI-1748-treated group. Thus, TgShSp1 oocyst infection is a suitable model to study both cerebral and ocular infection by T. gondii. BKI-1748 represents an interesting candidate for follow-up studies on neosporosis and toxoplasmosis in larger animal models.
Vaccination with Neospora caninum-cyclophilin and -profilin confers partial protection against experimental neosporosis-induced abortion in sheep
2021, Vaccine
Citation Excerpt :
Successful development of neosporosis vaccines using bacterial recombinant Neospora proteins has been lacking in both the target species- cattle and in small ruminant models such as sheep [1]. However, mice have been widely used as a model to evaluate neosporosis vaccine candidates [2–3]. Numerous Neospora vaccine candidates delivered as recombinant protein, viral vectors, or naked DNA have shown some degree of efficacy against experimental N. caninum infection in mice and hamsters (for review see [3–5]).
The purpose of this study was to evaluate the protective efficacy of a vaccine consisting of recombinant Neospora caninum-cyclophilin (NcCyP) and -profilin (NcPro) in sheep. At 42 d and 21 d prior to mating, adult Dorset ewes were immunized with the rNcCyP-rNcPro vaccine (Group 1) or co-purifying non-recombinant (NR) control vaccine (Group 2). At 90 days post-mating, all immunized ewes and were challenged by intravenous injection with 10⁶ Nesopora caninum Illinois tachyzoites (NcTZ). Significant protection (P < 0.05) was observed in Group 1 with 9 out of 13 ewes giving birth to live-born lambs (69.2%), whereas all Group 2 ewes aborted (6/6). Neospora caninum was detected by PCR in both fetal and placental tissues from all Group 2 aborting ewes and in the placental tissues of Group 1 aborting ewes. In contrast, tissues and placentas of Group 1 live-born lambs were Neospora DNA-negative. Immunoreactive Neospora antigens were demonstrated in placentas associated with abortions, but not in tissues of aborted fetuses or those of the live-born lambs and their associated placentas. Anti-NcCyP and anti-NcPro titers were high in sera from Group 1 ewes and were further boosted by challenge infection, resulting in long-lasting (≥14.5 mos.) elevated titers. Lambs born to Group 1 ewes also had high NcCyP and NcPro titers in pre-colostrum sera. Immunofluorescence staining (IFA) of NcTZ with Group 1 post-immunization sera revealed both surface and internal TZ staining, a pattern consistent with that observed with rabbit sera to rNcCyP or rNcPro. Infection of NR-vaccinated ewes produced high but transient anti-NcCyP and anti-NcPro Ab titers. The results indicate that the NcCyP-NcPro vaccine elicited strong anti-N. caninum responses and conferred significant protection against abortion and transplacental transmission of N. caninum TZ in sheep.
Shedding light on biochemical features and potential immunogenic epitopes of Neospora caninum SAG1: In silico study
2021, Informatics in Medicine Unlocked
Citation Excerpt :
It is noteworthy that acute Neospora infection can be limited through CD4+ Th1 responses and IFN-γ production along with a balanced Th2 response. However, whether a potential vaccine regimen should provoke a Th1 or Th2 CD4+ response is still controversial, because of large conflicting results both in cattle and mice as target species [54,63]. More standardized vaccine trials are demanded to enhance our knowledge on the exact role of different T-cell subsets in protection against N. caninum infection.
Vaccination is the only feasible way for appropriate prevention of Neospora caninum infection. The present in silico study was done to evaluate the physico-chemical properties and determine immunogenic epitopes of N. caninum SAG1 protein as a possible vaccine candidate. Web-based tools were used to predict physico-chemical properties, antigenicity, allergenicity, solubility, post-translational modification (PTM) sites, transmembrane domains and signal peptide, secondary and tertiary structures as well as intrinsically disordered regions, followed by identification and screening of potential linear and conformational B-cell epitopes and those peptides having affinity to bind mouse major histocompatibility complex (MHC) and cytotoxic T lymphocyte (CTL). The protein was stable in a test tube, had 319 residues with a molecular weight of 33.07 kDa, representing aliphatic index of 76.68 (thermotolerant) and GRAVY score of 0.031 (hydrophobic). There were 42 PTM sites and an N-terminally-located signal peptide in the sequence. Secondary structure comprised mostly by random coils, followed by strands and helices. Ramachandran plot of the refined model showed 71.7%, 24.9%, 3.0% and 0.4% residues in the favored, additional allowed, generously allowed and disallowed regions, correspondingly. Additionally, various potential B-cell (linear and conformational), CTL and MHC-binding epitopes were predicted for N. caninum SAG1. The findings of the present in silico study are a premise for vaccination strategies against neosporosis.

View all citing articles on Scopus

View full text

Invited ReviewNeospora caninum in non-pregnant and pregnant mouse models: cross-talk between infection and immunity

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Immune response to N. caninum infection in non-pregnant mice

Consequences of infection for pregnancy and the progeny

Where to go from here

Acknowledgements

Vaccine

Vet. Parasitol.

Exp. Parasitol.

Int. J. Parasitol.

Vaccine

Theriogenology

Int. J. Parasitol.

Int. J. Parasitol.

Int. J. Parasitol.

Biomed. Pharmacother.

Int. J. Parasitol.

Exp. Parasitol.

Exp. Parasitol.

Vet. Parasitol.

Exp. Parasitol.

Int. J. Parasitol.

Vet. Parasitol.

Int. J. Parasitol.

Exp. Parasitol.

Vet. Parasitol.

Vaccine

Exp. Parasitol.

Vaccine

Vet. Parasitol.

Int. J. Parasitol.

Int. J. Parasitol.

Vet. Parasitol.

Int. J. Parasitol.

Vaccine

Vet. Parasitol.

Int. J. Parasitol.

Vet. Immunol. Immunopathol.

Vet. Parasitol.

Role of the chemokine receptor CCR5-dependent host defense system in Neospora caninum infections

Parasite Vectors

Role of NK cells and gamma interferon in transplacental passage of Toxoplasma gondii in a mouse model of primary infection

Infect. Immun.

Role of gamma interferon and T cells in congenital Toxoplasma transmission

Parasite Immunol.

Characterisation of NcGRA7 and NcSAG4 proteins: immunolocalisation and their role in the host cell invasion by Neospora caninum tachyzoites

Acta Parasitol.

N-terminal fusion of a toll-like receptor 2-ligand to a Neospora caninum chimeric antigen efficiently modifies the properties of the specific immune response

Parasitology

The development of immune responses in Balb/c mice following inoculation with attenuated or virulent Neospora caninum tachyzoites

Parasite Immunol.

Immunization of BALB/c mice with killed Neospora caninum tachyzoite antigen induces a type 2 immune response and exacerbates encephalitis and neurological disease

Clin. Diag. Lab. Immunol.

Differential induction of TLR3-dependent innate immune signaling by closely related parasite species

PLoS One

The protozoan Neospora caninum directly triggers bovine NK cells to produce gamma interferon and to kill infected fibroblasts

Infect. Immun.

Vaccination of mice against experimental Neospora caninum infection using NcSAG1- and NcSRS2-based recombinant antigens and DNA vaccines

Parasitology

Adjuvant and immunostimulatory effects of a D-galactose-binding lectin from Synadenium carinatum latex (ScLL) in the mouse model of vaccination against neosporosis

Vet. Res.

Characterization of pathology and parasite load in outbred and inbred mouse models of chronic Neospora caninum infection

J. Parasitol.

Infected dendritic cells facilitate systemic dissemination and transplacental passage of the obligate intracellular parasite Neospora caninum in mice

PLoS One

Temporal distribution and parasite load kinetics in blood and tissues during Neospora caninum infection in mice

Infect. Immun.

Predominant role of interferon-gamma in the host protective effect of CD8(+) T cells against Neospora caninum infection

Sci. Rep.

Mucosal and systemic T cell response in mice intragastrically infected with Neospora caninum tachyzoites

Vet. Res.

Nucleotide-binding oligomerization domain-containing protein 2 prompts potent inflammatory stimuli during Neospora caninum infection

Sci. Rep.

Invited Review
Neospora caninum in non-pregnant and pregnant mouse models: cross-talk between infection and immunity