Control of Innate and Adaptive Immune Responses during Infectious Diseases ppt

Control of Innate and Adaptive Immune

Responses during Infectious Diseases

Julio Aliberti

Editor

Control of Innate and

Adaptive Immune Responses

during Infectious Diseases

Editor

Julio Aliberti

Associate Professor

Divisions of Molecular Immunology and Pulmonary Medicine

Cincinnati Children’s Hospital Medical Center and School of Medicine

University of Cincinnati

Cincinnati, OH, USA

[email protected]

ISBN 978-1-4614-0483-5 e-ISBN 978-1-4614-0484-2

DOI 10.1007/978-1-4614-0484-2

Springer New York Dordrecht Heidelberg London

Library of Congress Control Number: 2011936972

© Springer Science+Business Media, LLC 2012

All rights reserved. This work may not be translated or copied in whole or in part without the written

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v

Upon infection, pathogen and host perform a complex interaction that ultimately

aims to achieve elimination of the invading microbe with the least amount of dam￾age to host tissues and organs. Interestingly, both sides of this equation co-evolved

several mechanisms that mediate pathogen recognition, initiation and expansion of

immune responses, neutralization of toxic elements and elimination of replicating

organisms and finally healing and remodeling of damaged tissues. On one side

pathogens evolved mechanisms to evade recognition and killing, while on the other

side, host express numerous (sometimes redundant) mechanisms of recognition and

elimination of the pathogen. Nonetheless, it is clear that an absolute successful

strategy on the pathogen side would be lethal to both host and pathogen. Therefore,

several evasion mechanisms are seen among several microbes. The most successful

ones are not necessarily the most abundantly found within the host, but those that

can achieve transmission. On the other hand, hosts need a robust and extended

immune response in order to expand memory cells. This critical balance is where

the co-evolution between host and pathogens lies. This book covers several aspects

of induction, control and evasion of host immune response during infectious dis￾eases. Multiple aspects are covered and each chapter focuses on one prominent

infectious agent.

Cincinnati, OH Julio Aliberti

Preface

vii

1 Resolution of Inflammation During Toxoplasma gondii Infection ........ 1

Julio Aliberti

2 Mechanisms of Host Protection and Pathogen

Evasion of Immune Response During Tuberculosis .............................. 23

Andre Bafica and Julio Aliberti

3 NKT Cell Activation During (Microbial) Infection ............................... 39

Jochen Mattner

4 Regulation of Innate Immunity

During Trypanosoma cruzi Infection ....................................................... 69

Fredy Roberto Salazar Gutierrez

5 B Cell-Mediated Regulation of Immunity

During Leishmania Infection ................................................................... 85

Katherine N. Gibson-Corley, Christine A. Petersen,

and Douglas E. Jones

6 Control of the Host Response to Histoplasma Capsulatum .................... 99

George S. Deepe, Jr.

7 Modulation of T-Cell Mediated Immunity by Cytomegalovirus .......... 121

Chris A. Benedict, Ramon Arens, Andrea Loewendorf,

and Edith M. Janssen

8 T Cell Responses During Human Immunodeficiency

Virus (HIV)-1 Infection ............................................................................ 141

Claire A. Chougnet and Barbara L. Shacklett

Index ................................................................................................................. 171

Contents

ix

Julio Aliberti, Ph.D. Associate Professor, Divisions of Molecular Immunology

and Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center

and School of Medicine, University of Cincinnati, Cincinnati, OH, USA

[email protected]

Ramon Arens Division of Developmental Immunology, La Jolla Institute

for Allergy and Immunology, La Jolla, CA, USA

Andre Bafica, M.D., Ph.D. Assistant Professor, Department of Microbiology,

Immunology and Parasitology, Federal University of Santa Catarina,

Florianopolis, SC, Brazil

[email protected]

Chris A. Benedict Division of Immune Regulation, La Jolla Institute

for Allergy and Immunology, La Jolla, CA, USA

[email protected]

Claire A. Chougnet Division of Molecular Immunology, Cincinnati Children’s

Hospital Research Foundation and Department of Pediatrics, University of

Cincinnati, Cincinnati, OH, USA

[email protected]

George S. Deepe. Jr, M.D. Professor, Veterans Affairs Hospital, Cincinnati, OH,

USA; Division of Infectious Diseases, University of Cincinnati College of Medicine,

Cincinnati, OH, USA

[email protected]

Katherine N. Gibson-Corley Department of Veterinary Pathology,

College of Veterinary Medicine, Iowa State University, Ames, IA, USA

Fredy Roberto Salazar Gutierrez, M.D., Ph.D. Assistant Professor,

School of Medicine, Antonio Nariño University, Bogotá, Colombia

[email protected]

Contributors

x Contributors

Edith M. Janssen Division of Molecular Immunology, Cincinnati Children’s

Hospital Research Foundation, University of Cincinnati College of Medicine,

Cincinnati, OH, USA

[email protected]

Douglas E. Jones Department of Veterinary Pathology, College of Veterinary

Medicine, Iowa State University, Ames, IA, USA

[email protected]

Andrea Loewendorf Division of Molecular Immunology, La Jolla Institute

for Allergy and Immunology, La Jolla, CA, USA

Jochen Mattner, M.D. Professor of Molecular Microbiology and Infection

Immunology, University Hospital of Erlangen, Microbiology Institute –

Clinical Microbiology, Immunology and Hygiene, Erlangen, Germany

[email protected]

Christine A. Petersen Department of Veterinary Pathology,

College of Veterinary Medicine, Iowa State University, Ames, IA, USA

Barbara L. Shacklett Department of Medical Microbiology and Immunology,

School of Medicine, University of California, Davis, CA, USA

J. Aliberti (ed.), Control of Innate and Adaptive Immune Responses 1

during Infectious Diseases, DOI 10.1007/978-1-4614-0484-2_1,

© Springer Science+Business Media, LLC 2012

Abstract Upon Toxoplasma gondii host infection, a powerful immune response

takes place in order to contain dissemination of the parasite and prevent mortality.

Once parasite proliferation is contained by IFN-J-dependent responses, nevertheless ,

parasite immune escape prevents complete clearance characterizing the onset of the

chronic phase of infection, with a continuous (and powerful) cell-mediated immu￾nity. Such potent responses are kept under tight control by several, non-redundant

mechanisms that control pro-inflammatory mediators. Including cytokines, such as

members of the IL-10 family, TGF-beta, the membrane receptors, ICOS, CTLA4

and a class of anti-inflammatory eicosanoids, the lipoxins. In this chapter we address

the host strategies that keep pro-inflammatory responses under control during chronic

disease. On the other hand, we approach the perspective of the pathogen, which

pirates the host’s machinery to its own advantage as a part of the pathogen’s immune￾escape mechanisms.

1.1 Introduction

Toxoplasmosis is caused by the protozoan parasite, Toxoplasma gondii. The pathogen

can be found worldwide and is particularly prevalent in the United States, where it

is estimated that more than 60 million people may be infected. Among those who

are infected, few develop symptoms due to healthy immune system that usually

prevents the parasite from causing illness. Nevertheless, within the high risk group

are pregnant women and individuals with compromised immune systems.

J. Aliberti (*)

Divisions of Molecular Immunology and Pulmonary Medicine,

Cincinnati Children’s Hospital Medical Center and School of Medicine,

University of Cincinnati, Cincinnati, OH, USA

e-mail: [email protected]

Chapter 1

Resolution of Inflammation

During Toxoplasma gondii Infection

Julio Aliberti

2 J. Aliberti

Felines, including the house cat are definitive hosts in which it is observed the

sexual stages of T. gondii and thus, are considered to be the main parasite reservoirs.

Cats become infected with T. gondii by carnivorism (Fig. 1.1). After tissue cysts or

oocysts are ingested, viable organisms are released and invade epithelial cells of the

small intestine, where they undergo an asexual cycle followed by a sexual cycle and

then form oocysts, which can be excreted. The unsporulated oocyst takes 1–5 days

after excretion to sporulate (become infective). Although cats shed oocysts for only

1–2 weeks, large numbers may be shed.

Oocysts can survive in the environment for several months and are remarkably

resistant to disinfectants, freezing, and drying, but are killed by heating to 70°C for

10 min. The persistency of oocysts in the environment may enhance the infectious

potential of the parasite.

Humans may acquired T. gondii via different routes (Fig. 1.1):

(a) Ingestion of: raw or undercooked and infected meat containing Toxoplasma

cysts; oocysts from fecally contaminated hands or food;

(b) Organ transplantation or blood transfusion from infected humans;

(c) Transplacental transmission from an infected mother; and

(d) Accidental inoculation of tachyzoites.

predation

Ingestion of oocysts

Ingestion of infected raw meat

or water/food contaminated

with oocysts

Congenital

transmission

Feces

Fig. 1.1 Toxoplasma gondii life cycle. Cats become infected with T. gondii through predation of

infected mice or rats. After cysts or oocysts are ingested the organisms are released and spread

throughout the small intestine and then form oocysts, which are excreted and can potentially sur￾vive for long periods in the environment. Human acquire infection via in several routes: ingestion

of infected food containing Toxoplasma cysts; ingestion of oocysts from contaminated hands or

food; organ transplantation or blood transfusion from infected humans; transplacental transmis￾sion from an infected mother; and accidental inoculation of tachyzoites

1 Resolution of Inflammation During Toxoplasma gondii Infection 3

Toxoplasma gondii, a protozoan apicomplexa parasite is highly virulent and can

potentially invade and subsequently replicate within any nucleated host cell. Under

natural conditions infection occurs by ingestion of parasite oocyst-contaminated

food or water. Oocysts are complex structures formed in the digestive tract of the

definitive host – felines which protect the parasites from heat and dehydration and

can remain infective within the environment for long periods of time. Once ingested,

oocyst rupture occurs within the host digestive system and the released parasites

enter host cells through an active process mediated by the apical complex (Morisaki

et al. 1995). Host cells include epithelial cells, resident macrophages and dendritic

cells (Fig. 1.1, Life Cycle). Once intracellular, the parasites (tachyzoites) quickly

replicate. Although definitive evidence is still required, it is proposed that circulat￾ing infected host cells (probably macrophages or DCs) might mediate spread of the

parasite to several organs, including the liver. One current hypothesis proposes that

the acute phase of infection resolves when the remaining fast-replicating parasites

switch, probably as a response to immune attack, to a slow replicating form known

as bradyzoites and seclude themselves in cysts in certain tissues, such as the central

nervous system (CNS) and the retina (known as chronic or persistent infection)

(Black and Boothroyd 2000).

For a long time it was widely accepted that cysts containing bradyzoites were latent,

biologically inactive structures that eventually died off or in some cases re-activated

parasite replication. Today, however this concept has been challenged as it has been

shown that cysts are dynamic structures, where parasites convert to tachyzoites. The

conclusion is that this “dripping” effect in which tachyzoites are slowly released, con￾tinuously stimulating immune response. Therefore, when immune suppression caused

by drugs or other infections, such as HIV, can lead to reversion from bradyzoites back

to the fast replicating tachyzoites, which rupture cysts causing local tissue necrosis,

thus characterizing the main pathology resulting from this infection. If reactivation

occurs in the CNS, it is often lethal. During the early years of the AIDS epidemic,

encephalitis due to reactivation of chronic T. gondii infection was one of the most

relevant pathologies affecting immuno-depressed patients (Martinez et al. 1995).

In nature, the main route for T. gondii transmission is through predation (i.e.

felines preying on rodents), therefore an evolutionary advantage would be among

pathogens that populate the host and simultaneously provide conditions to protect

the host to carry as many parasites without killing it. In other words, this means to

proliferate while promoting host survival. To achieve this, the parasite has evolved

several mechanisms to induce a powerful immune response by the host, which pre￾vents host death by controlling parasite growth. However, to avoid the potential

collateral damage of such powerful pro-inflammatory reaction, the pathogen sub￾verts the immune system allowing it to persist through the chronic phase of the

disease, which can last for many years (Hay and Hutchison 1983). Herein, we dis￾cuss the immune response triggered by T. gondii and how hosts and pathogens make

use of immune-regulatory pathways to promote host survival, which increases the

probability of parasite transmission.

4 J. Aliberti

1.2 Experimental T. gondii Infection

1.2.1 Microbial Recognition and IL-12 Induction

A balanced interrelationship between host and parasite is highly dependent on

the early induction of immune response after infection. Too much immune response

and pathogen is swiftly cleared without causing disease. On the other hand, the

absence of a proper timely host response may lead to uncontrolled pathogen replica￾tion and spread, often leading to the death of the host. Nevertheless, this is an

over-simplification of the rather complex scenarios that take place during T. gondii

infection. Although significant protection is achieved after infection, a relevant

proportion of invading parasites evade immune effector mechanisms, i.e. tachyzoites

turn infected cells incapable to secrete pro-inflammatory mediators (Walker et al.

2008), bradyzoites, hidden within tissue cysts populate immune privileged sites,

such as the retina or the CNS. Therefore, T. gondii parasites can persist in the host

even in the presence highly powerful immune response. To add further complexity

to this interaction, several lines of evidence indicate that without innate immune

responses, such as following NK-cell depletion, the initial IFN-J-dependent control

of parasite replication is compromised and, in the case of NK-cell-depletion of

T-cell-deficient mice, host resistance is lost resulting in host death, which indicates an

important role for NK cells in the induction of a response (Sher et al. 1993; Hunter

et al. 1994).

IL-12 is a cytokine produced during pathogen recognition that is essential to

trigger both NK cell as well as T cell-derived IFN-J production during T. gondii

infection. The biological relevance of this cytokine was evidenced by the finding that

IL-12-deficient animals are extremely susceptible to T. gondii infection (Gazzinelli

et al. 1994).

B cells, macrophages, neutrophils and DCs are known to produce IL-12 in vitro

and in vivo (Denkers 2003). During T. gondii infection, macrophages, neutrophils

and DCs can all produce detectable amounts of IL-12 after T. gondii infection

(Denkers 2003). However, DCs – abundant producers of IL-12 in vivo – are the most

relevant cell population for the development of a parasite-specific type 1 immune

response. Reis e Sousa and colleagues observed that splenic mouse CD8D+

DCs

produce IL-12 in response to T. gondii in the absence of co-stimulatory signals (Reis e

Sousa et al. 1997). While macrophages require a cognate priming signal, i.e. IFN-J

and neutrophil IL-12 production levels are relatively low when compared to DCs.

In summary, DCs can either activate the immune system by recognition of parasite￾derived molecules or can harbor initial replication of the intracellular parasites.

A cellular homogenate from culture-derived tachyzoites (STAg) was used in

order to decipher which are the parasite components and their respective host recep￾tors involved in DC IL-12 induction by T. gondii. Such approach seemed feasible

since STAg was capable to induce markedly higher levels of IL-12 from in vitro

stimulated splenic DCs than when the same cell populations are exposed to several

other microbial products. Although the mechanisms underlying such responses are