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Infection & Immunity (I&I)
Mission statement
The program aims to discover principles of infection and associated pathobiology at the cellular,
organ, host, and population level with the goal to develop novel infection intervention and
prevention strategies.
Program outline
Aim of the program
Infectious diseases are a continuous threat to human, animal, and economic health. Control of the
(re-)emergence and persistence of infectious agents requires detailed knowledge of all aspects of
the entire infection chain, i.e. genome plasticity and virulence potential of infectious agents,
cellular infection mechanisms, innate and adaptive host defense, and infection dynamics. The
overall aim of this research program is to unravel principles of infection at the individual and
community level to facilitate targeted development of novel infection intervention and prevention
strategies.
Research focus
Principles of infection and intervention and prevention are investigated using infectious agents
that have with zoonotic potential and/or are of major (future) veterinary, public health or
economic relevance.
Program design
In general, infection cycles involve contact with and adaptation of infectious agents to distinct
niches in the host, breaching of tissue barriers, multiplication, evasion of the innate and adaptive
host defense, and spread to a new host. Development of novel infection intervention and
prevention strategies thus requires detailed knowledge of the pathogen, its host, the interplay
between pathogen and host, and the interaction of the host with the environment, including other
hosts. Unraveling of principles of infection and the associated pathology requires a
multidisciplinary approach involving microbiology, immunology, cell biology, biochemistry,
pathology, animal health and epidemiology. The I&I program covers and integrates this expertise,
providing the optimal setting to achieve our goals. To accommodate the complexity of the infection
cycle and to facilitate the development of novel infection control tools, the research program is
divided into three coherent research lines that each target key steps in the infection process:

Cellular infection mechanisms

Host defense

Infection dynamics
The scope of the respective research lines is given below.
I&I Research line 1: Cellular infection mechanisms
Departments of I&I, PB, and B&C
For most pathogens direct interaction with host cells and exploitation of host cell biology are
essential in the establishment of an infection. This research line aims to dissect for selected sets of
pathogens the molecular mechanisms that drive the cellular infection and associated changes in
host cell biology.
Objectives and approach
1. nidovirus and influenza infections
Nidoviruses (corona-, toro-, and arteriviruses) and influenza virus cause infections in various
animals and humans (SARS, influenza). Objectives are the unraveling of the mechanisms of (i)
virus cell entry, (ii) replication, (iii) transcription, (iv) gene expression and (v) progeny virus
assembly. Recent development of tools (infectious clones) and strategies (targeted RNA
recombination) for the genetic manipulation of viruses greatly facilitates fundamental studies as
well as the development of vaccines and expression vectors.
2. Bacterial mucosal infections
Campylobacter and Salmonella frequently colonize animals and are the major bacterial foodborne human pathogens. Objectives are to dissect (i) the bacterial virulence repertoire, (ii)
relevant host cell receptors, (iii) the intracellular fate, and (iv) survival strategies for these
pathogens in different host species (chicken, human). This approach adds the discovery of novel
potential targets of infection intervention and candidate vaccine antigens.
3. host cell membrane dynamics
Modulation of host cell membrane dynamics (e.g. interactions with membrane transport
machinery and lipid rafts) is a typical trait of many pathogens. Objectives are to define cell
membrane dynamics related to host-pathogen interactions via (i) characterization of
microdomains from Golgi membranes, (ii) unraveling of the role of the Golgi complex in the
membrane dynamics and pathogenesis, and (iii) elucidation of membrane dynamics involved in
communication between immune-competent organelles including plasma membranes,
phagosomes, and endosomes. This is accomplished using viral and bacterial cellular infection
systems.
Coherence of the research line
The common theme of this research line is the interaction of infectious agents with host cells. Via
a comparative infection biology approach using selected sets of different classes of infectious
agents (bacteria, viruses), a comprehensive view of the cellular infection strategies of pathogens is
obtained. Elucidation of host cell receptors, signaling pathways, virulence factors, and mechanisms
via which pathogens modulate host response and cell membrane dynamics is essential for the
rational design of novel infection intervention strategies and vaccines, and understanding of
fundamental cell biology principles and associated pathology. A main challenge is to translate the
molecular pathogen-host cell knowledge to the dynamics of the natural infection at the organand host-level (research line 3).
Key publications

de Vries E, Tscherne DM, Wienholts MJ, Cobos-Jiménez V, Scholte F, García-Sastre A,
Rottier PJ, de Haan CA (2011) Dissection of the influenza A virus endocytic routes reveals
macropinocytosis as an alternative entry pathway. PLoS Pathog 7: e1001329.

van der Meer-Janssen YP, van Galen J, Batenburg JJ, Helms JB (2010) Lipids in hostpathogen interactions: pathogens exploit the complexity of the host cell lipidome. Prog
Lipid Res 49:1- 26.

Reggiori F, Monastyrska I, Verheije MH, Calì T, Ulasli M, Bianchi S, Bernasconi R, de Haan
CA, Molinari M (2010) Coronaviruses hijack the LC3-I-positive EDEMosomes, ER-derived
vesicles exporting short-lived ERAD regulators, for replication. Cell Host Microbe 7: 500508.

Zeng Q, Langereis MA, van Vliet AL, Huizinga EG, de Groot RJ (2008) Structure of
coronavirus hemagglutinin-esterase offers insight into corona and influenza virus
evolution. Proc Nat Acad Sci USA 105: 9065-9069.
I&I Research line 2: host defense
Departments of I&I, B&C, FAH
The host immune response towards infectious agents is a key element of infection biology. Vice
versa, unraveling of pathogen – host cell interactions leads to the discovery of novel molecular
immunology principles. This research line focuses on the innate and adaptive host response and
embodies the entire epithelial - DC - B/T cell axis. Understanding of the interplay between
infectious agents and the host defense facilitates rational immunomodulation and successful
vaccine design and immunotherapy.
Objectives and approach
1. Innate defense
The innate host defense is increasingly appreciated as the first barrier for infectious agents and
as a key element that orchestrates the adaptive immune response. This research field is rapidly
gaining a rather central position in the molecular infection biology research program as it
bridges the knowledge of the infectious agents per se with that of the host response, the
susceptibility to infection, and infection-associated immunopathology. Primary objectives are
identification of (i) innate sensing receptors for pathogens in different hosts (pigs, chicken,
bovine, human, mouse), (ii) the regulation of the activation status and cross-talk between
signaling pathways, and (iii) the nature and efficacy of innate effector molecules (e.g. antimicrobial
peptides, collectins, cytokines, chemokines). Research includes cloning, identification and
functional analysis of pathogen recognition receptors (PRR, e.g. Toll-like receptors, type
C-lectin receptors, collectins) and their ligands, modulation of PRR function by environmental
signals, and regulation of the adaptive immune response (T and B cell function) by innate
signals.
2. Adaptive immune response
Understanding of the mechanisms that direct the antigen-specific immune response is extremely
valuable to vaccine design and understanding of pathogen-associated immunopathology.
Primary objectives are unraveling of (i) regulatory mechanisms of antigen presentation by
MHC class I and MHC class II, (ii) the role of exosomes in antigen presentation, memory, and
tolerization, and their potential as immunomodulatory tools, (iii) pathogen-directed modulation
of antigen-specific immunity, and (iv) the regulation of immunity by environment signals (cell
stress, heat shock proteins, probiotics). Experiments involve both in vitro and in vivo analysis
of immune cells of human, bovine, chicken and mouse species exposed to defined antigens
and/or infected with the above-mentioned pathogens with zoonotic potential.
3. Immunomodulation
Knowledge of the factors that direct the host defense provides the opportunity to modulate the
immune response to our benefit. This is achieved by (i) identification of natural adjuvants of
microbial origin (such as LPS) which adds rational vaccine design, (ii) targeted modification of
the cell environment (e.g. via probiotics, antimicrobial peptides), and (iii) rational modulation
of the immune response using defined microbial molecules. Analysis of immunopathology
associated with infections further adds to unravel the principles of immune regulation.
4. Protection‑inducing antigens
The main objective here is to (i) identify candidate vaccine antigens via analysis of immune
responses during natural and experimental infections (FIPV, Campylobacter, M.
paratuberculosis, influenza virus, PRRSV). This approach complements the targeted search
for candidate vaccine antigens and key virulence components of research line 1.
Coherence of the research line
This research line shows strong coherence as innate and adaptive immunity, immunomodulation,
immunopathology, and vaccine development are fully complementary but inherently dependent
research topics.
Key publications

de Zoete MR, Bouwman LI, Keestra AM, van Putten JPM (2011) Cleavage and activation of
a Toll-like receptor by microbial proteases. Proc Natl Acad Sci U S A 108: 4968-4973.

de Jong A, Peña-Cruz V, Cheng TY, Clark RA, Van Rhijn I, Moody DB (2010) CD1aautoreactive T cells are a normal component of the human alpha beta T cell repertoire. Nat
Immunol 11: 1102-1109.

Nolte-’t Hoen EN, Buschow SI, Anderton SM, Stoorvogel W, Wauben MH (2009) Activated
T cells recruit exosomes secreted by dendritic cells via LFA-1. Blood 113:1977-1981.
I&I Research line 3: Infection Dynamics
Departments of I&I, FAH, IRAS
Infections result from a dynamic interplay between pathogen and host communities that live in
distinct environments. Crucial in the establishment, persistence, and transmission of infectious
agents are (i) the structure, biology, and adaptation potential of infectious agents, (ii) the natural
architecture of the infection niche in the host, (iii) the genetic background and immune status of
individuals and a population as a whole, and (iv) the environmental conditions outside the host.
This research line addresses infection dynamics and aims to define common principles of (re)
emergence, course, persistence, and cycles of infection at the organ, host, and population level as
well as evaluation of novel infection prevention and intervention strategies.
Objectives and approach
1. Pathogen plasticity
The gene repertoire, mechanisms of environmental gene regulation, horizontal gene transfer,
and the adaptive potential of infectious agents determine virulence, infection niche, persistence,
and spread of infection including the crossing of species barriers. Objectives are to (i) identify
relevant genetic differences between related strains and species, (ii) unravel mechanisms of
phenotype variation that influences organ- and host-tropism, (iii) define the adaptation potential
to changing host environments including intestinal ecology, and (iv) analyze mutations and
gene flow (e.g. virulence and drug resistance genes) that influence infection and therapy. The
work follows a genomics and molecular approach to identify stable markers of virulence that
adds diagnostics, epidemiology, drug development, and vaccine design.
2. Complex infection models
Infection dynamics becomes particularly evident in the setting of the natural infection when all
players that determine the outcome of infection are present. Hence, important objectives are to
(i) develop and (ii) apply well-defined infection models that enable translation of laboratory
findings to the natural setting and vice versa, and (iii) to understand the infection-associated
pathology in the context of the pathogen and its environment. Established infection models
include FIPV in cats, Campylobacter in chicken, and M. paratuberculosis in livestock.
3. Population infection dynamics
Detailed knowledge of the interaction between pathogen and host communities forms the basis
of transmission studies and facilitates the development of concepts, strategies, and tools to
prevent infection or to alleviate or cure the disease. Field observations may add to identify
susceptible populations, transmission routes, host determinants that provide natural resistance
against infection, and virulence determinants that contribute to the spread of an infection.
Objectives are (i) to develop methodological (quantitative) tools to integrate knowledge and
explain observed population effects, and (ii) to unravel transmission mechanisms underlying
the occurrence, evolution, spread, and control of infectious diseases.
4. Molecular infection prevention and intervention
Emerging infectious diseases and the steady increase in drug resistance urges development of
novel molecular infection prevention and intervention methods (in addition to conventional
measures to improve hygiene and prevent transmission). Primary objectives in this direction are
(i) to evaluate the efficacy of probiotics, collectins, anti-microbial peptides and developed
vaccines (see also research line 2), and (ii) to explain the effects on infection dynamics at the
population, animal, organ and cellular level (iii) to explore the spread of antibiotic resistance
and to develop alternative for the use of antibiotics.
Coherence of the research line
This research line focuses on infection dynamics at the molecular, animal and population level.
This complementary approach benefits development as well as evaluation of novel infection
intervention and prevention tools.
Key publications

van Duijkeren E, Ten Horn L, Wagenaar JA, de Bruijn M, Laarhoven L, Verstappen K, de
Weerd W, Meessen N, Duim B (2011) Suspected horse-to-human transmission of MRSA
ST398. Emerg Infect Dis 17: 1137-1139.

van Eijk M, Bruinsma L, Hartshorn KL, White MR, Rynkiewicz MJ, Seaton BA, Hemrika W,
Romijn RA, van Balkom BW, Haagsman HP (2011) Introduction of N-linked glycans in the
lectin domain of surfactant protein D: impact on interactions with influenza A viruses. J
Biol Chem 286: 20137-20151.

Davis SA, Trapman JP, Leirs H, Begon M & Heesterbeek JAP (2008) The abundance
threshold for plague as a critical percolation phenomenon. Nature 454: 634-637.

Juhász-Kaszanyitzky E, Jánosi S, Somogyi P, Dán A, van der Graaf-van Bloois L, van
Duijkeren E, Wagenaar JA (2007) MRSA transmission between cows and humans. Emerg.
Infect. Dis. 213, 630-632.
Program organization
The program combines research efforts of the Departments of Infectious Diseases and
Immunology, Biochemistry and Cell Biology, Pathobiology, and Farm Animal Health, with links to
the Institute for Risk Assessment Sciences. The program is embedded in the university research
focus area ‘Infection and Immunity’, with links to the research focus area ‘Epidemiology’.
I&I contact
Prof.dr. H.P. Haagsman (program coordinator)