Unifying Microbial Mechanisms

Shared Strategies of Pathogenesis

Michael F. Cole

• Publisher: Garland Science
• Year: 2019
• ISBN:
  9780429557835
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Microbiology
• Index: Biological Sciences

Microbial pathogenesis is the study of the mechanisms by which microbes (bacteria, viruses, protozoa, and multicellular parasites) cause infectious disease and make their hosts (humans) ill. Bacterial infections we thought were easily treatable are again a huge cause for concern with the well-publicized rise of antibiotic resistance. There are very few effective antiviral drugs and we live with the threat of epidemics such as bird flu and the outbreaks of viruses such the recent (and ongoing) Ebola crisis. Parasitic diseases such as malaria continue to pose a heavy burden in the developing world and with climate change could spread into the developed world. There is therefore an urgent need to understand microbial mechanisms, with research programmes and university courses dedicated to the subject.

Chapter 1: Introduction to Pathogenesis

INTRODUCTION

The aim of this text, is to examine and discuss common themes in microbial pathogenesis. Despite the class of pathogen – whether virus, bacterium, fungus or parasite – they all cause tissue injury and evade the host immune system in much the same ways and attack the same targets. Therefore, it seems only sensible to discuss pathogenic mechanisms in the context of all of these classes of pathogens. With rare exception, texts on pathogenesis have focused on a single class of pathogen, such as bacteria, without conveying any sense that the pathogenic mechanisms described can just as easily be applied to any other class of pathogen. Pathogenics is at the interface of microbiology and immunology because it considers the properties of a microorganism that harm the host and the innate and acquired host defence mechanisms that can neutralise them. The relationship between the pathogen and host is dynamic and reflects thrust and counter thrust. The fulcrum of this interaction can be moved to benefit either combatant by, for example, enhancing or compromising the host immune system or by the acquisition of new genes or loss of existing genes by the microorganism. We will return to this concept later. Because one cannot consider the microbe in the absence of the host, most texts of microbial pathogenesis feel obliged to devote a considerable amount of the text to basic immunology and basic microbiology as a prelude to the consideration of the mechanisms of pathogenesis of microbes. However, there is a plethora of excellent immunology and microbiology texts, both concise and comprehensive, that are superior to the coverage of these disciplines in pathogenesis texts. It is reasonable to say that students should be competent in immunology and microbiology before embarking on a course in microbial pathogenesis. For these reasons, basic microbiology and immunology are not covered in this book beyond that essential to understand particular pathogenic mechanisms.

There are three goals in the study of the pathogenesis of microbes. The first is to identify the aetiological agent of a particular infectious disease, the second is to determine what property or properties of the microorganism and the host allow it to cause disease, and the third is to find methods of neutralising and eradicating the agent by the use of antimicrobial agents and by harnessing the host immune system.

HENLE-KOCH POSTULATES AND EVOLVING VIEWS OF INFECTIOUS DISEASE CAUSATION

Criteria for identifying the aetiology of infectious diseases first were presented in an address given by Robert Koch to the Tenth International Congress of Medicine in Berlin in 1890. They are as follows:

1. The parasite occurs in every case of the disease in question and under circumstances which can account for the pathological changes and clinical course of the disease.

2. The parasite occurs in no other disease as a fortuitous and nonpathogenic parasite.

3. After being fully isolated from the body and repeatedly grown in pure culture, the parasite can induce the disease anew.

These postulates were based on Koch’s study of tuberculosis and anthrax caused by the bacteria Mycobacterium tuberculosis and Bacillus anthracis, respectively. Later others added a fourth postulate, viz:

4. The parasite should be re-isolated from the susceptible host (postulate 3) and shown to be identical to that isolated originally (postulate 1).

Although these postulates are adequate to describe some infectious agents, Koch and others realised that failure to fulfil the postulates does not exclude a microbe from being the aetiologic agent of an infectious disease. For example, viruses and some bacteria that cannot be grown on artificial media fail postulate 3, and resident microbes that cause disease in immunocompromised individuals, so-called opportunistic pathogens, fail postulate 2. The advent of the application of molecular biological techniques to the study of microbial pathogenesis resulted in a revised set of molecular Koch’s postulates formulated by Falkow (1988) that took advantage of these new techniques. Falkow’s molecular postulates are listed below.

1. The phenotype or property under investigation should be associated with the pathogenic members of a genus or pathogenic strains of a species.

2. Specific inactivation of the gene(s) associated with the suspected virulence trait should lead to a measurable loss in pathogenicity or virulence, or the gene(s) associated with the supposed virulence trait should be isolated by molecular methods. Specific inactivation or deletion of the gene(s) should lead to loss of function in the clone.

3. Reversion or allelic replacement of the mutated gene(s) should lead to restoration of pathogenicity, or the replacement of the modified gene(s) for its allelic counterpart in the strain of origin should lead to loss of function and loss of pathogenicity or virulence. Restoration of pathogenicity should accompany the reintroduction of the wild-type gene(s).

To allow sequence-based methods to establish causal relationships between microbes and disease in cases where the suspected aetiologic agent cannot be cultivated, Fredricks and Relman (1996) formulated a set of guidelines that are listed below:

1. A nucleic acid sequence belonging to a putative pathogen should be present in most cases of an infectious disease. Microbial nucleic acids should be found preferentially in those organs or gross anatomic sites known to be diseased, and not in those organs that lack pathology.

2. Fewer, or no, copy numbers of pathogen-associated nucleic acid sequences should occur in hosts or tissues without disease.

3. With resolution of disease, the copy number of pathogen-associated nucleic acid sequences should decrease or become undetectable. With clinical relapse, the opposite should occur.

4. When sequence detection predates disease, or sequence copy number correlates with severity of disease or pathology, the sequence–disease association is more likely to be a causal relationship.

5. The nature of the microorganism inferred from the available sequence should be consistent with the known biological characteristics of that group of organisms.

6. Tissue–sequence correlates should be sought at the cellular level: Efforts should be made to demonstrate specific in situ hybridization of microbial sequence to areas of tissue pathology and to visible microorganisms or to areas where microorganisms are presumed to be located.

7. These sequence-based forms of evidence for microbial causation should be reproducible.

What is notable about the three sets of criteria listed above is their focus on the microbe without regard to the role of the host immune system in pathogenesis. However, the immune status of the host clearly modulates pathogenicity. Pathogenicity is defined in this text as the capacity of a microbe to cause damage to the host. Virulence is defined as the relative capacity of a microbe to cause damage to the host. In a series of papers, Casadevall redefined the basic concepts of virulence and pathogenicity by integrating microbe-centric and host-centric approaches to pathogenesis into a damage–response framework based on the following three tenets:

1. Microbial pathogenesis is the outcome of an interaction between the host and a microbe and is attributable to neither the microbe nor the host alone.

2. The pathological outcome of the microbe–host interaction is determined by the amount of damage to the host.

3. The damage to the host can result from microbial factors and/or the host response.

Casadevall’s damage–response framework can be described by the parabolic curve shown in Figure 1.1. The position of the base of the parabola is variable and, whereas host damage can occur throughout the continuum of the host response (x axis), it is maximal at both extremes. Both weak and strong host responses are defined by both qualitative and quantitative aspects of the host immune response. Figure 1.2 shows six classes of pathogenic microbes fitted to the damage–response framework. Figure 1.2a shows situation in which a microbial factor, for example, an exotoxin, completely responsible for host damage and in which it binds to its receptor before the host can produce antibodies to neutralise it. The exotoxin in this example is, by definition, a true virulence determinant/factor in that the exotoxin-producing microbe is rendered avirulent if the gene encoding the exotoxin is inactivated or if the exotoxin is neutralised by host antibodies. It may surprise the reader to realise how few microbial components fulfil these criteria. There is but one more microbial component that fulfils these criteria and it is the capsule. All other components/molecules that are thought to contribute to pathogenicity but have not fulfilled the criteria stated above are more accurately termed determinants of pathogenicity. Table 1.1 lists vaccines currently approved for use in the United States. It will be noted that vaccines exist for certain pathogenic bacteria and viruses only. Currently there are no antifungal or anti-parasite vaccines. All of the vaccines against virus infections employ either killed or attenuated virus. All but two of the bacterial vaccines are toxoids (toxins that have been rendered nontoxic by chemical means but retain their antigenicity) or capsular polysaccharides. Only the pertussis vaccine and the meningococcus serogroup B vaccine contain defined vaccine antigens other than exotoxins or capsules.

Figure 1.1 Basic parabolic curve of the damage–response framework. (From Casadevall, A. and Pirofski, L.A., Nat. Rev. Microbiol., 2003, 1, 17–24.)

Figure 1.2 The six classes of pathogenic microorganisms according to the damage–response framework. (From Casadevall, A. and Pirofski, L.A., Nat. Rev. Microbiol., 2003, 1, 17–24.)

microbe	vaccine antigen(s)
adenovirus	live adenovirus type 4 and type 7
ant...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Dedication
• Table of Contents
• Preface
• Acknowledgement
• Chapter 1: Introduction to Pathogenesis
• Chapter 2: Normal Microbiotas of the Human Body
• Chapter 3: Biofilms
• Chapter 4: Adhesion to Host Surfaces
• Chapter 5: Facilitated Cell Entry
• Chapter 6: Exotoxins and Endotoxins
• Chapter 7: Extracellular Degradative Enzymes
• Chapter 8: Evasion of the Human Innate Immune System
• Chapter 9: Evasion of the Human Adaptive Immune System
• Chapter 10: Persistent and Latent Infections
• Index