Neospora Caninum: Infection and Immunity

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Immunological Responses and Immune Defense Mechanisms".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 25439

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Guest Editor
CIISA - Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal
Interests: neosporosis; toxoplasmosis; besnoitiosis; African swine fever; host-parasite interactions; immunity
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Guest Editor
Institute of Parasitology, Vetsuisse Faculty, University of Berne, 3012 Bern, Switzerland
Interests: neosporosis; toxoplasmosis; besnoitiosis; echinococcosis; drugs; vaccines; host-parasite interactions
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
SALUVET Group, Animal Health Department, Faculty of Veterinary Sciences, Complutense University of Madrid, 28040 Madrid, Spain
Interests: protozoan diseases in domestic ruminants; host–parasite interactions; in vitro and in vivo models; drugs; vaccines

Special Issue Information

Dear Colleagues,

Neospora caninum is an apicomplexan parasite that was misdiagnosed as Toxoplasma gondii until the 1980s, but has subsequently been shown to be responsible for abortion, stillbirth, and birth of weak offspring in dogs, cattle, and many other species. N. caninum and T. gondii are phylogenetically closely related and share many morphological, structural, and biological features, but they also have important differences in terms of pathophysiology and host–parasite interactions. Most notably, canids can act as definitive hosts for N. caninum, which is not infective in humans, while only feline hosts allow sexual development of T. gondii, which has enormous zoonotic potential, showing that the two parasites are distinct biological entities. These similarities and differences have profound implications for the design of management control measures and for the development of new therapeutic options and vaccine candidates.

N. caninum can infect a wide range of domestic and wildlife mammals, but infection in cattle and, more recently, in sheep is of high economic concern. Indeed, N. caninum constitutes one of the major causes of infective reproductive losses in ruminants, most notably, bovines.

Neospora caninum infected animals commonly do not present clinical signs other than occasional abortion, stillbirth, or birth of weak calves, but the parasite is efficiently transmitted from the dam to the offspring, perpetuating the infection in the herd. Therefore, management control options are expensive and difficult to implement. Vaccination is generally considered the most cost-effective strategy to control the disease. However, an inactivated vaccine introduced to the market years ago was withdrawn due to ambiguous results, and despite considerable efforts, no other vaccines have been made available so far. Therapeutic options, such as the use of drugs, have previously not been regarded as attractive alternatives, due to the necessary withdrawal periods for meat and milk consumption and because safe and efficacious compounds have not been available on the market.

Overall, the development of viable prophylactic and therapeutic interventions to combat neosporosis depends largely on deepening the knowledge on the mechanisms underlying the interaction of N. caninum with its hosts. On the cellular level, this includes host cell entry and establishment in the host cell, replication, dissemination to other cells, and stage conversion. On the immunological level, the most relevant aspects are how the host innate defense mechanisms sense the parasite, the roles of parasite virulence factors and antigens, immunomodulation during gestation, and the acquired immune response profiles that are relevant for protection. Since vertical transmission has a central role in maintaining infection in cattle herds, vaccines and drugs must be safe during gestation and must eliminate vertical transmission. Considering the difficulties associated with in vivo experiments using cattle, the definition, characterization, and standardization of pregnant and non-pregnant alternative animal infection models is important in this context. However, alternative models must be critically evaluated in terms of their relevance. This Special Issue “Neospora caninum: infection and immunity” aims to compile original research papers and review articles on these topics to offer a comprehensive overview of the subject.

Dr. Alexandre Leitão
Prof. Andrew Hemphill
Prof. Luis-Miguel Ortega-Mora
Guest Editors

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Keywords

  • invasion
  • host cell modification
  • proliferation
  • egress
  • stage conversion
  • innate immunity
  • acquired immunity
  • humoral response
  • cytokines
  • in vitro and in vivo models
  • therapy
  • vaccines

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Published Papers (7 papers)

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Research

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11 pages, 262 KiB  
Article
Detection of Neospora caninum Infection in Aborted Equine Fetuses in Israel
by Monica Leszkowicz Mazuz, Lea Mimoun, Gili Schvartz, Sharon Tirosh-Levy, Igor Savitzki, Nir Edery, Shlomo E. Blum, Gad Baneth, Nicola Pusterla and Amir Steinman
Pathogens 2020, 9(11), 962; https://doi.org/10.3390/pathogens9110962 - 19 Nov 2020
Cited by 11 | Viewed by 2226
Abstract
In horses, Neospora caninum and Neospora hughesi have been associated with fetal loss, and neurological disease, respectively. This study investigated the role of Neospora spp. infection in equine abortion in Israel. The presence of anti-Neospora spp. antibodies was evaluated in 31 aborting [...] Read more.
In horses, Neospora caninum and Neospora hughesi have been associated with fetal loss, and neurological disease, respectively. This study investigated the role of Neospora spp. infection in equine abortion in Israel. The presence of anti-Neospora spp. antibodies was evaluated in 31 aborting mares by indirect fluorescent antibody test (IFAT) and the presence of parasite DNA in their aborted fetuses was evaluated by polymerase chain reaction (PCR), using two target loci (ITS1 and Nc5). The seroprevalence found in aborting mares was 70.9% and the prevalence by DNA detection in the aborted fetuses was 41.9%. Transplacental transmission from positive mares to their fetuses was 45.4% (10/22), while 33.3% (3/9) of fetuses of seronegative mares also tested positive for Neospora. The use of two PCR targets improved the sensitivity of parasite detection, and positive samples were identified by sequence analyses as N. caninum. These finding suggest that N. caninum could be a significant cause of abortion in horses, and that transplacental transmission in horses is an important way of transmission of N.caninum. The results presented here demonstrated the necessity to use several tests concurrently, including serological and molecular assays in order to confirm the involvement of Neospora in mare abortions. Full article
(This article belongs to the Special Issue Neospora Caninum: Infection and Immunity)
10 pages, 838 KiB  
Article
Proteomic Characterization of Host-Pathogen Interactions during Bovine Trophoblast Cell Line Infection by Neospora caninum
by Javier Regidor-Cerrillo, Dong Xia, Laura Jiménez-Pelayo, Marta García-Sánchez, Esther Collantes-Fernández, Nadine Randle, Jonathan Wastling, Luis-Miguel Ortega-Mora and Pilar Horcajo
Pathogens 2020, 9(9), 749; https://doi.org/10.3390/pathogens9090749 - 15 Sep 2020
Cited by 7 | Viewed by 2665
Abstract
Despite the importance of bovine neosporosis, relevant knowledge gaps remain concerning the pathogenic mechanisms of Neospora caninum. Infection of the placenta is a crucial event in the pathogenesis of the disease; however, very little is known about the relation of the parasite [...] Read more.
Despite the importance of bovine neosporosis, relevant knowledge gaps remain concerning the pathogenic mechanisms of Neospora caninum. Infection of the placenta is a crucial event in the pathogenesis of the disease; however, very little is known about the relation of the parasite with this target organ. Recent studies have shown that isolates with important variations in virulence also show different interactions with the bovine trophoblast cell line F3 in terms of proliferative capacity and transcriptome host cell modulation. Herein, we used the same model of infection to study the interaction of Neospora with these target cells at the proteomic level using LC-MS/MS over the course of the parasite lytic cycle. We also analysed the proteome differences between high- (Nc-Spain7) and low-virulence (Nc-Spain1H) isolates. The results showed that mitochondrial processes and metabolism were the main points of Neospora-host interactions. Interestingly, Nc-Spain1H infection showed a higher level of influence on the host cell proteome than Nc-Spain7 infection. Full article
(This article belongs to the Special Issue Neospora Caninum: Infection and Immunity)
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20 pages, 3202 KiB  
Article
Impact of Neospora caninum Infection on the Bioenergetics and Transcriptome of Cerebrovascular Endothelial Cells
by Hany M. Elsheikha, Mamdowh Alkurashi, Suzy Palfreman, Marcos Castellanos, Kenny Kong, Evita Ning, Nashwa A. Elsaied, Kalotina Geraki and William MacNaughtan
Pathogens 2020, 9(9), 710; https://doi.org/10.3390/pathogens9090710 - 28 Aug 2020
Cited by 5 | Viewed by 2768
Abstract
In this work, the effects of the protozoan Neospora caninum on the bioenergetics, chemical composition, and elemental content of human brain microvascular endothelial cells (hBMECs) were investigated. We showed that N. caninum can impair cell mitochondrial (Mt) function and causes an arrest in [...] Read more.
In this work, the effects of the protozoan Neospora caninum on the bioenergetics, chemical composition, and elemental content of human brain microvascular endothelial cells (hBMECs) were investigated. We showed that N. caninum can impair cell mitochondrial (Mt) function and causes an arrest in host cell cycling at S and G2 phases. These adverse effects were also associated with altered expression of genes involved in Mt energy metabolism, suggesting Mt dysfunction caused by N. caninum infection. Fourier Transform Infrared (FTIR) spectroscopy analysis of hBMECs revealed alterations in the FTIR bands as a function of infection, where infected cells showed alterations in the absorption bands of lipid (2924 cm−1), amide I protein (1649 cm−1), amide II protein (1537 cm−1), nucleic acids and carbohydrates (1092 cm−1, 1047 cm−1, and 939 cm−1). By using quantitative synchrotron radiation X-ray fluorescence (μSR-XRF) imaging and quantification of the trace elements Zn, Cu and Fe, we detected an increase in the levels of Zn and Cu from 3 to 24 h post infection (hpi) in infected cells compared to control cells, but there were no changes in the level of Fe. We also used Affymetrix array technology to investigate the global alteration in gene expression of hBMECs and rat brain microvascular endothelial cells (rBMVECs) in response to N. caninum infection at 24 hpi. The result of transcriptome profiling identified differentially expressed genes involved mainly in immune response, lipid metabolism and apoptosis. These data further our understanding of the molecular events that shape the interaction between N. caninum and blood-brain-barrier endothelial cells. Full article
(This article belongs to the Special Issue Neospora Caninum: Infection and Immunity)
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16 pages, 2346 KiB  
Article
Modulation of Leptin and Leptin Receptor Expression in Mice Acutely Infected with Neospora caninum
by Luzia Teixeira, Alexandra Correia, Bárbara M. Oliveira, Ana Pinto, Paula G. Ferreira and Manuel Vilanova
Pathogens 2020, 9(7), 587; https://doi.org/10.3390/pathogens9070587 - 17 Jul 2020
Cited by 3 | Viewed by 2676
Abstract
Neospora caninum is an apicomplexan parasite that in cattle assumes particular importance, as it is responsible for abortions reported worldwide. Leptin is an adipokine mainly secreted by adipocytes, which beside its role in maintaining metabolic homeostasis also has important effects in both innate [...] Read more.
Neospora caninum is an apicomplexan parasite that in cattle assumes particular importance, as it is responsible for abortions reported worldwide. Leptin is an adipokine mainly secreted by adipocytes, which beside its role in maintaining metabolic homeostasis also has important effects in both innate and adaptive immunity. In previous work, we showed that mice chronically infected with N. caninum had elevated serum leptin levels. Here, we sought to assess whether acute infection with N. caninum infection influenced the production of this adipokine as well as leptin receptor mRNA levels. Our results show that acute infection with N. caninum led to decreased leptin serum levels and mRNA expression in adipose tissue. A decrease in leptin receptor transcript variant 1 mRNA (long isoform) and leptin receptor transcript variant 3 mRNA (one of the short isoforms) expression was also observed. An increase in the number of cells staining positive for leptin in the liver of infected mice was observed, although this increase was less marked in Interleukin (IL)-12/IL-23 p40-deficient mice. Overall, our results show that N. caninum infection also influences leptin production during acute infection. Full article
(This article belongs to the Special Issue Neospora Caninum: Infection and Immunity)
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19 pages, 5491 KiB  
Article
Neospora caninum: Structure and Fate of Multinucleated Complexes Induced by the Bumped Kinase Inhibitor BKI-1294
by Pablo Winzer, Nicoleta Anghel, Dennis Imhof, Vreni Balmer, Luis-Miguel Ortega-Mora, Kayode K. Ojo, Wesley C. Van Voorhis, Joachim Müller and Andrew Hemphill
Pathogens 2020, 9(5), 382; https://doi.org/10.3390/pathogens9050382 - 16 May 2020
Cited by 17 | Viewed by 3072
Abstract
Background: Bumped kinase inhibitors (BKIs) are potential drugs for neosporosis treatment in farm animals. BKI-1294 exposure results in the formation of multinucleated complexes (MNCs), which remain viable in vitro under constant drug pressure. We investigated the formation of BKI-1294 induced MNCs, the re-emergence [...] Read more.
Background: Bumped kinase inhibitors (BKIs) are potential drugs for neosporosis treatment in farm animals. BKI-1294 exposure results in the formation of multinucleated complexes (MNCs), which remain viable in vitro under constant drug pressure. We investigated the formation of BKI-1294 induced MNCs, the re-emergence of viable tachyzoites following drug removal, and the localization of CDPK1, the molecular target of BKIs. Methods: N. caninum tachyzoites and MNCs were studied by TEM and immunofluorescence using antibodies directed against CDPK1, and against NcSAG1 and IMC1 as markers for tachyzoites and newly formed zoites, respectively. Results: After six days of drug exposure, MNCs lacked SAG1 surface expression but remained intracellular, and formed numerous zoites incapable of disjoining from each other. Following drug removal, proliferation continued, and zoites lacking NcSAG1 emerged from the periphery of these complexes, forming infective tachyzoites after 10 days. In intracellular tachyzoites, CDPK1 was evenly distributed but shifted towards the apical part once parasites were extracellular. This shift was not affected by BKI-1294. Conclusions: CDPK1 has a dynamic distribution depending on whether parasites are located within a host cell or outside. During MNC-to-tachyzoite reconversion newly formed tachyzoites are generated directly from MNCs through zoites of unknown surface antigen composition. Further in vivo studies are needed to determine if MNCs could lead to a persistent reservoir of infection after BKI treatment. Full article
(This article belongs to the Special Issue Neospora Caninum: Infection and Immunity)
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Review

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18 pages, 3839 KiB  
Review
Research into Neospora caninum—What Have We Learnt in the Last Thirty Years?
by Michael P. Reichel, Lloyd C. Wahl and John T. Ellis
Pathogens 2020, 9(6), 505; https://doi.org/10.3390/pathogens9060505 - 23 Jun 2020
Cited by 20 | Viewed by 6396
Abstract
Background: Neospora caninum has been recognised world-wide, first as a disease of dogs, then as an important cause of abortions in cattle for the past thirty years. Over that time period, there have been improvements in the diagnosis of infection and abortion, new [...] Read more.
Background: Neospora caninum has been recognised world-wide, first as a disease of dogs, then as an important cause of abortions in cattle for the past thirty years. Over that time period, there have been improvements in the diagnosis of infection and abortion, new tests have been developed and validated, and it is timely to review progress to date. Methods: Bibliometric methods were used to identify major trends and research topics present in the published literature on N. caninum. The tools used were SWIFT-Review, VOSviewer and SciMAT, along with the published papers found in the MEDLINE, Dimensions and Web of Science databases. A systematic review of the published Neospora literature (n = 2933) was also carried out via MEDLINE and systematically appraised for publications relevant to the pathogenesis, pathology and diagnosis of Neospora abortions. Results: A total of 92 publications were included in the final analysis and grouped into four main time periods. In these four different time periods, the main research themes were “dogs”, “abortion”, “seroprevalence” and “infection”. Diagnostics, including PCR, dominated the first two time periods, with an increased focus on transmission and abortions, and its risk factors in cattle. Conclusions: Longitudinal analyses indicated that the main themes were consistently investigated over the last 30 years through a wide range of studies, with evolving emphasis initially on dogs and diagnostic test development, followed by application to cattle, the identification of the risk factors leading to abortion, and in the latter time periods, an understanding of the immunity and a search for vaccines. Full article
(This article belongs to the Special Issue Neospora Caninum: Infection and Immunity)
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44 pages, 1036 KiB  
Review
From Signaling Pathways to Distinct Immune Responses: Key Factors for Establishing or Combating Neospora caninum Infection in Different Susceptible Hosts
by Ragab M. Fereig and Yoshifumi Nishikawa
Pathogens 2020, 9(5), 384; https://doi.org/10.3390/pathogens9050384 - 16 May 2020
Cited by 29 | Viewed by 4598
Abstract
Neospora caninum is an intracellular protozoan parasite affecting numerous animal species. It induces significant economic losses because of abortion and neonatal abnormalities in cattle. In case of infection, the parasite secretes numerous arsenals to establish a successful infection in the host cell. In [...] Read more.
Neospora caninum is an intracellular protozoan parasite affecting numerous animal species. It induces significant economic losses because of abortion and neonatal abnormalities in cattle. In case of infection, the parasite secretes numerous arsenals to establish a successful infection in the host cell. In the same context but for a different purpose, the host resorts to different strategies to eliminate the invading parasite. During this battle, numerous key factors from both parasite and host sides are produced and interact for the maintaining and vanishing of the infection, respectively. Although several reviews have highlighted the role of different compartments of the immune system against N. caninum infection, each one of them has mostly targeted specific points related to the immune component and animal host. Thus, in the current review, we will focus on effector molecules derived from the host cell or the parasite using a comprehensive survey method from previous reports. According to our knowledge, this is the first review that highlights and discusses immune response at the host cell–parasite molecular interface against N. caninum infection in different susceptible hosts. Full article
(This article belongs to the Special Issue Neospora Caninum: Infection and Immunity)
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