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92 Pathogenesis and Immunology

Chapter 4: Pathogenesis and Immunology

Georg Behrens and Matthias Stoll

Introduction

The influenza virus is notoriously known for its unique ability to cause recurrent epidemics and global pandemics during which acute febrile respiratory illness occurs explosively in all age groups. Two qualities of influenza account for much of the epidemiological spread of the virus. First, is the ability to emerge and circulate in avian or porcine reservoirs by either genetic reassortment or direct transmission and subsequently spread to humans at irregular intervals. Second, is the fast and unpredictable antigenic change of important immune targets once the virus has become established in a human.

A highly contagious virus causing extensive morbidity and major case fatality rates is an archetypal anxiety. Influenza has the potential to create such a scenario. The influenza virus, as a pathogenic agent for humans, has been circulating in the human population since at least the sixteenth century (Cox & Kawaoka 1998) leading to recurrent epidemics of febrile respiratory disease every 1 to 3 years. In addition, each century has seen some pandemics rapidly progressing to involve all parts of the world due to emergence of a novel virus to which the overall population holds no immunity. The characteristics of pandemics include occurrence outside the usual season, extremely rapid transmission with concurrent outbreaks throughout the globe, and high attack rates in all age groups with high mortality rates even in healthy young adults. Given the growing world population and international travel and tourism, impending pandemic influenza outbreaks gain the potential to spread even more rapidly. In order to understand the background of this global epidemic threat more thoroughly, this chapter aims to describe both the pathogenesis of the disease and the contest between the virus and the immune system.

Pathogenesis

The pathogenicity and virulence of the influenza virus is determined by several interacting factors:

a)Host factors:

Presence of target receptors on host cells

Availability of enzymes in host cells which are essential for viral entry and replication

State of immunocompetence of the individual host

Specific immunity against certain viral epitopes in the individual host and target population

Ability of the immune system to control the viral replication effectively without causing serious collateral damage for the host by its inflammatory response

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b)Viral factors:

Ability to bind to host cells

Ability of virus shedding

Restriction of cytopathogenic effects to allow for an appropriate balance between viral replication and control by the host

Escape from immunosurveillance by evolution of antigenic variation driven by selective pressure of the immune response

Escape from immunosurveillance by recombination with different virus strains from zoonotic disease

Modulation of the immune response to attenuate effective host defense mechanisms

Viral entry: How does the virion enter the host?

The predominant way in which influenza is transmitted is from person to person by aerosols and droplets. Influenza then enters the host through the respiratory tract. In a human lung there are about 300 million terminal sacs, called alveoli, that function in gaseous exchange between inspired air and the blood. The total absorptive area of the human lungs ranges from 80-120 m2. The resting ventilation rate in humans is about 6 liters of air per minute, which introduces large numbers of foreign particles and aerosolized droplets potentially containing virus into the lungs. Deposition of foreign particles depends on their size: inhalation of very small particles does not result in absorption through the alveoli or bronchial system. Small droplets with a diameter of approximately 1 to 4 µm precipitate in the small airways. Much larger particles are either not able to enter the respiratory system or are deposited in the upper respiratory tract (Figure 1A).

Numerous host defense mechanisms including mechanical barriers block respiratory tract infection. The respiratory tract is covered with a mucociliary layer consisting of ciliated cells, mucus-secreting cells and glands (Figure 1 B). Foreign particles in the nasal cavity or upper respiratory tract are trapped in mucus, carried back to the throat, and swallowed. From the lower respiratory tract foreign particles are brought up by the ciliary action of epithelial cells. In the alveoli that lack cilia or mucus, macrophages are responsible for destroying particles (Figure 1).

Binding to the host cells

The main targets of the influenza virus are the columnar epithelial cells of the respiratory tract. These cells may be susceptible to infection if the viral receptor is present and functional. Thus, viral receptors are determinants of tropism. However, this simplified model is often insufficient to explain viral tropism since the receptor distribution in the host is generally more widespread than the observed virus tropism.

94 Pathogenesis and Immunology

Figure 1. Sites of influenza entry in the respiratory tract. (A) The anatomical and functional structures of the human airways are shown. Influenza first infects the upper airway and the ciliated cells in the bronchus and bronchioli. Resulting clinical syndromes include tracheitis, bronchitis, bronchiolitis, and bronchopneumonia. The adaptive immune response is initiated in lymph nodes along the airways. (B) The respiratory epithelia is especially equipped to defend from incoming pathogens by a layer of mucus (bronchus), ciliated cells (bronchus and bronchioli), and alveolar macrophages (alveoli).

In influenza infection, the receptor binding site of viral hemagglutinin (HA) is required for binding to galactose bound sialic acid on the surface of host cells (Weis 1988). Certain areas of the binding site of HA are highly conserved between subtypes of the influenza virus (Daniels 1984). Hosts may prevent the attachment by several mechanisms: (1) specific immune response and secretion of specific IgA antibodies, (2) unspecific mechanisms, such as mucociliary clearance or production of mucoproteins that able to bind to viral hemagglutinin, and (3) genetic diversification of the host receptor (sialic acid), which is highly conserved in the same species, but differs between avian and human receptors (Matrosovich 2000). As a result, the avian virus needs to undergo mutations at the receptor binding site of hemagglutinin to cross the interspecies barrier between birds and humans. In pigs, polymorphisms of sialic acid species and linkage to galactose of both humans and birds are co-expressed in the tissue. Therefore, co-infection with avian and human influenza can occur in pigs and allow genetic reassortment of antigenic properties of both species in the co-infected cells. Recently, it has been shown that certain avian influenza viruses in human and birds are able to bind to different target cells (Matrosovich 2004). This could explain the observation of several cases since the end of the 1990s with transmission of avian influenza directly from poultry to humans. H5N1 and some other subtypes of influenza A virus are able to bind to receptors in the human eye (Olofson 2005).

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As essential as the binding of the influenza virus is its cleavage from the binding site at the host cell. Cleavage is the functional role of viral neuraminidase (Chen 1998). The virulence of the influenza virus depends on the compatibility of neuraminidase with hemagglutinin. A virulent virus which has undergone mutations in the hemagglutinin needs compensatory mutations in the neuraminidase to maintain its virulence (Baigent & McCauley 2003, Hulse 2004). As a consequence, viral fitness and virulence were found to be reduced in influenza viruses resistant to neuraminidase inhibitors (Yen 2005).

Once the cell membrane and the virus have been closely juxtaposed by virusreceptor interaction, the complex is endocytosed. Importing H+ ions into the late endocytic vesicles as a physiologic event then acidifies the interior. Upon acidification, the viral HA undergoes a conformational rearrangement that produces a fusiogenic protein. The loop region of the HA becomes a coiled coil eventually bringing the viral and endosomal membranes closer so that fusion can occur. To allow release of viral RNA into the cytoplasm, the H+ ions in the acidic endosome are pumped into the virion interior by the M2 ion channel. As a result, viral RNA dissociates from M1 by disrupting the low pH-sensitive interaction between the M1 and ribonuclein complex after fusion of the viral and endosomal membranes. The viral RNA is then imported in an ATP-dependent manner into the nucleus for transcription and translation (Flint 2004).

Figure 2: Replication cycle of influenza A virus. Binding and entry of the virus, fusion with endosomal membrane and release of viral RNA, replication within the nucleus, synthesis of structural and envelope proteins, budding and release of virions capable of infecting neighboring epithelial cells (Modified from Cox & Kawaoka 1997)