The Enemy
Human pathogens consist of four groups: 
Bacteria
Viruses
Fungi
Parasites
The Immune System responds to each of these invaders in different ways reflecting differences in their biological behaviour. 
 
The Prokaryotic Cell and the Eukaryotic Cell 
The definitive difference between prokaryotic and eukaryotic cells is that eukaryotic cells have organelles; membrane-bound structures such as the nucleus. In the prokaryote, all of the components are within the cell cytoplasm. A typical prokaryotic cell has a cytoplasmic membrane that separates the inside of the cell from the outside, a rigid cell wall that provides structure, up to 10,000 ribosomes and a single (usually) circular molecule of DNA (the bacterial chromosome). 
 
The presence of organelles defines the eukaryote - the genetic material is within a membrane-bound nucleus. Most eukaryotes have multiple molecules of DNA (46 in humans) - the chromosomes. 
 
Bacteria 
Bacteria are single-celled prokaryotic organisms. they are generally divided into two groups; Gram +ve and Gram -ve . This division is on the basis of their response to staining with a purple-coloured dye - the Gram Stain.3 Microbiologically the Gram Stain is very important. Gram negative bacteria have a cell membrane, then outside of that a peptiglycan cell wall and then a second outer-membrane. The Gram positives lack the second membrane and have a thicker cell wall. The presence of the outer membrane is the reason these bacteria stain negative as the stain binds to the cell wall, the outer membrane prevents this from happening. Immunologically the Gram status of a bacteria is unimportant in terms of the immune response. However it is important when bacteria infect the blood (septicaemia). Gram -ve septicaemia is potentially far more lethal than infection by a Gram +ve organism. The outer membrane of the Gram -ve bacteria contains a molecule termed Lipopolysaccharide or LPS. The LPS molecule triggers an immense immune reaction mediated by the cytokine TNF-a which results in septic shock. 
 
Clinically the Gram status of a bacteria can be very useful. Together with the morphology it can be diagnostic; for example Gram +ve diplococci (pairs of round bacteria) is a Streptococcus species whist bunches of Gram +ve cocci indicates that the infective organism is a Staphylococcus, and in a immune-competent individual it is very likely to be Staphylococcus aureus. Similarly, Gram -ve rods found in cerebrospinal fluid are likely to be Neisseria meningitidis, although they could also be Escherichia coli; Streptococcus pneumoniae is eliminated as a possibility. 
 
Fungi 
The fungi are a very large diverse group of organisms ranging from the yeast Sacchromyces cerevisiae (responsible for alcohol production) to moulds and the garden mushroom. Several fungi are medically important, most prominent of these is Candida albicans that causes candidiasis (thrush). Several other common infections are caused by fungi such are ring worm (Microsporum) and Athlete's Foot (Epidermophyton and Trichophyton). Fungi are eukaryotic organisms. This is important clinically as it makes treatment more difficult. Antibiotics kill bacteria because structures within the prokaryotic cell are sufficiently different from the eukaryotic cell that compounds that are toxic to the bacteria are non-toxic or significantly less toxic to the human host. As fungi are eukaryotes it is inherently more difficult to find or manufacture compounds that are selectively toxic to the fungi and not to the patient. There are a number of anti-fungal drugs available but superficial infection is much more easily treated than systemic infection. 
 
Parasites 
Strictly, the term parasite refers to any organism that lives off another and can cause damage to the host. Hence, all of the pathogens are parasites. However in microbiological and immunological terms it is used to apply to the infective organisms that are not bacteria, viruses or fungi. 
 
Parasitology thus covers are a very diverse group of organisms. Primarily the parasites are divided into protozoa (single celled parasites) and Helminths (multicellular). All parasites are eukarotic cells and hence have the same difficulty with antibiotics that fungi have. 
 
The Helminths are microscopic worms: there are Nematodes (round worms), and Platyhelminths (flat worms) which are divided into Cestodes (tapeworms) and Trematodes (flukes). 
 
The Protazoa are divided into four groups: Amoebae, Flagellates, Sporozoa and Cilliates. The Amoeba Acanthomaeba is medically important as it can cause blindness when it infects the eye. This particular infection is caused by contact lens wearers cleaning their lenses with tap water. Amongst the flagellates is Giardia, a water born infection that causes gastroenteritis and is very common in the developing world. Within the group sporozoa are the plasmodia and the biggest killer amongst all infective diseases is a plasmodia disease - malaria. Malaria is caused by four different species of plasmodia; Plasmodium falciparum, P. ovale, P. vivax and P. malariae. It is estimated that malaria kills between 1 and 2 million people every year,2 mostly in sub-Saharan Africa and most victims are under five years of age. There is a second peak of infection and death with malaria and that is amongst pregnant women. This is thought to be due to a degree of immuno-compromise caused by pregnancy. 
 
Viruses 
Viruses are more difficult to define than the other groups. However the definition of viruses as submicroscopic obligate intracellular parasites,5 whilst considered inadequate for virology, is sufficient from an immunological perspective. One of the inadequacies of this definition is that it does not differentiate the virus from obligate intracellular bacteria. 
Descriptively, viruses are tiny infective organisms. They are made up of proteins and other molecules that contain a genome. In order to reproduce they must infect a living cell. They then use the cellular 'machinery' of the infected cell to replicate their genome and to produce the molecules necessary to assemble viral particles. Some viruses are cytotoxic - they kill the infected cell - whilst others form a relatively stable interaction with the cell. All cellular organisms seem to have viruses that infect them. 
 
The difficulties associated with treating fungal and parasitic infections are even greater with viral infections. Whilst compounds that are active against fungal or parasitic metabolism may be harmful to human cells, viral metabolism is human metabolism because of the way the virus 'hijacks' the host cell. There are two groups of drug that go some way to resolving this problem. The first is the anti-retroviral drugs used to treat HIV infection. There are three different classes of anti-retrovirals but they all work on the principal of targeting viral enzymes. There are some steps in the HIV life-cycle that depends on viral enzymes rather than host ones and this is where the drugs work. 
Acyclovir and its related compounds make up the other group. Acyclovir is cytotoxic to human cells. However the drug taken is a pro-drug; it is inactive. A viral enzyme (a thymadine kinase) is needed to activate acyclovir. This particular thymadine kinase is only found in Herpes-virus infected cells. Hence only infected cells are killed. This is essentially the strategy taken by the immune system.
 
Whilst antibodies have some role in that they bind to viral particles and prevent them infecting cells, this makes only a small contribution to viral immunity. The major response of the immune system to viral infection is to kill the infected cells by a number of mechanisms. 
 
Exceptions 
The above classification of pathogens into four groups is very useful as the immune response is essentially the same for any organism within each group. The biological process for fighting one bacterial infection is much the same as another, similarly the mechanism for killing one virus is essentially identical to that for any other virus. 
There are some important exceptions, such as the Rickettsia species and the Mycobacteria which includes Mycobacterium tuberculosis (the main cause of human tuberculosis) and Mycobacterium leprae (leprosy). These bacteria are intracellular parasites. Some are obligate intercellur parasites (can only grow within a host cell) and other are facultative. Generally, oligate intracellular parasites have all the mechanisms found in other bacteria expect the ability to produce ATP for energy. As a consequence, they can only grow within a host cell. Immunologically this is important as, whilst these organisms are bacteria, an effective immune response to them involves the same as aspects of the immune system as that to used to fight viruses. The parts of the immune system that deal with most bacterial infections would be useless against these organisms as it operates entirely outside of the host cells. There are also intracellular plasmodia and fungi that infect humans.
Summary 
 	Bacteria	Viruses	Fungi	Parasites	
Cell Type	prokaryotic	none	eukaryotic	eukaryotic	
Intracellular / extracellular	both	intracellular	extracellular	both	
Unicellular / multicellular	unicellular	none	both	both	
Primarily immune response	humoral	CMI	both	both	
Size	1-5mm	0.02-0.3 mm	mm – mm	mm – mm	
Examples of human pathogens	S. aureus
N. Menigitidis	Herpes
HIV	Candida albicans	P. falciparum