Intestinal dendritic cells: key players in the innate immune control of  Cryptosporidium parvum infection in neonates

Dendritic cells present in the intestinal epithelium play a key role in the innate control of infection. This finding has been obtained by scientists working on an animal model of cryptosporidiosis in the Joint Research Unit for Infectiology and Public Health (UMR 1282 ISP) in Tours. These results open new avenues for the control of this zoonosis.

Iléon de veau infecté par  CRYPTOSPORIDIUM PARVUM . Microscopie électronique à balayage.. © INRA, GAILLARD-MARTINI Brigitte
Updated on 05/30/2014
Published on 05/30/2014

Cryptosporidiosis is an enteric disease that affects both human and animal populations and is mainly found in developing countries.  However, wealthier countries are not spared, and although human cases are recorded in the USA or Europe each year, it is mainly farmed livestock, and particularly ruminants, that pay a heavy price for this infection. Cryptosporidium parvum, a protozoan, is the causal agent of this disease which preferentially affects newborns.  By colonising the intestinal epithelium, the parasite causes profuse diarrhoea and subsequent death due to acute dehydration.

Very few therapeutic compounds have been available to date to control this parasite due to its specific metabolic pathway that diverges from that of other coccidians Furthermore, no effective vaccine has been developed.  Indeed, animals are infected during the first days after birth.  Maternal vaccination is not able to transmit to the newborn an effective protective immunity against the parasite, and neonatal vaccination does not trigger a sufficiently rapid immune response against this protozoan.  It is therefore necessary to develop new defence strategies.

 

 

Understanding the specificities of the immune system of newborns so that it can be reinforced

 

In the context of a thesis project,  in the “Apicomplexa and mucosal immunology” team of the Joint Research Unit for Infectiology and Public Health, scientists focused on the mechanisms involved in the resistance against C. parvum that allow adults to resist  natural infection while neonates remain highly susceptible. The ultimate objective of this study was to identify the " immune related cellular deficiency"   present in neonates and to stimulate young animals using methods other than vaccination.

The scientists worked on an animal model (mouse pups) which fairly represents the infective kinetics that occur in children and young ruminants.  Histological studies of the intestinal mucosa from mouse pups revealed a marked deficiency of CD103+ dendritic cells when compared to resistant adults.

 

The crucial role of CD103+ dendritic cells

 

The team was able to show in several ways that low levels of dendritic cells explained the vulnerability of newborns to cryptosporidiosis.  For example, when dendritic cells were increased artificially by the injection of factors favouring their development, the young animals became much more resistant to the infection.  On the other hand, if these cells were depleted artificially, the young animals were no longer able to protect themselves against the infection.  During infection by C. parvum, enterocytes in the intestinal epithelium secrete chemokines (soluble substances for cell signalling) which attract dendritic cell precursors present in the blood.  The CD103+ dendritic cells recruited in the infected area then start to secrete the anti-parasite compounds which are essential to the protective mechanism.

 

The research team would like to enhance the defences of newborns by encouraging the recruitment of intestinal dendritic cells and activating them to reduce the severity of infections due to the protozoan Cryptosporidium parvum.

This work is now being pursued in order to determine whether these promising results in mice can be transposed to ruminants.

Contact(s)
Scientific contact(s):

  • Fabrice LAURENT (33 22 47 42 77 51 ) Apicomplexans and Mucosal Immunity Team (AMI), Joint Research Unit for Infectiology and Public Health (UMR1282)
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Animal Health
Associated Centre(s):
Val de Loire

The two weapons of the immune system

The mammalian immune system displays two types of response to control pathogens: one innate and the other adaptive.  The so-called innate response can rapidly, but non-specifically, recognise infective agents by recognising molecular motifs that are common to a large number of microbial agents, or MAMPs (Microbe Associated Molecular Pattern). Examples of these MAMPs include the lipopolysaccharides of Gram negative bacteria, or nucleic acid motifs (RNA or DNA) of viruses.  Dendritic cells and macrophages strongly express the receptors for these MAMPs, or PRR (Pattern Recognition Receptors). Once activated by microbial ligands, by contact or through the release of soluble mediators, these cells in turn activate other populations inherent in the innate immune response such as NK (Natural Killer) cells, or influence development of the adaptive immune response.  This response, which develops during a second stage, is specific to the pathogen initially recognised and is endowed with a memory so that the body can efficiently control any infection by the same infective agent (through the production of antibodies or the lysis of infected cells by cytotoxic lymphocytes). 

For further information

  • Lantier L, Lacroix-Lamande´ S, Potiron L, Metton C, Drouet F, Guesdon W, Gnahoui-David A, Le Vern Y, Deriaud E, Fenis A, Rabot S, Descamps A, Werts C and Laurent F*. (2013) Intestinal CD103+ Dendritic Cells Are Key Players in the Innate Immune Control of Cryptosporidium parvum Infection in Neonatal Mice. PLoS Pathog 9(12): e1003801. doi:10.1371/journal.ppat.1003801