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Department of Pathology
Osmania Medical College
• Infectious agents have probably always caused disease in humans.
• Smallpox has been described in ancient Egyptian and Chinese writings and may have been
responsible for more deaths than all other infectious diseases combined.
• There is evidence that malaria and poliomyelitis have existed since ancient times.
• In the 14th Century, the bubonic plague, or Black Death, killed about 20 million people in
• In the 20th Century, the 1918 influenza may have killed up to 50 million people worldwide
• Close to 20 million people have died of AIDS to date.
• Bacteria were discovered in 1675 by Antony van Leeuwenhoek, but it wasn’t until 1876 that a German physician named
Robert Koch first demonstrated that specific diseases are associated with particular microorganisms.
• Koch developed a set of criteria to show that anthrax, a disease of cattle, was caused by a specific bacterium, named
Bacillus anthracis, and that tuberculosis was caused by a separate distinct bacterium.
• Koch presented his discovery of Mycobacterium tuberculosis in a lecture in March of 1882.
• He brought his entire laboratory setup to the lecture hall and demonstrated his procedures for his audience, inviting them
to check his findings themselves.
• His methods were so innovative that his criteria still are useful today in identifying disease-causing agents.
• Difficulties in applying these criteria can arise, however, for agents that are difficult to grow in culture or where a suitable,
susceptible experimental host cannot be found. This is an especially difficult situation, and raises ethical concerns, where
humans are the only known host.
• Robert Koch was awarded the Nobel Prize in Physiology and Medicine in 1905 for his work in tuberculosis.
• Koch developed four criteria to demonstrate that a specific disease is caused by
a particular agent.
• The specific agent must be associated with every case of the disease.
• The agent must be isolated from a diseased host and grown in culture.
• When the culture-grown agent is introduced into a healthy susceptible host, the
agent must cause the same disease.
• The same agent must again be isolated from the infected experimental host.
Definitions and Terms
• Disease – a pathological condition of body parts or tissues characterized by an identifiable
group of signs and symptoms.
• Infectious disease – disease caused by an infectious agent such as a bacterium, virus,
protozoan, or fungus that can be passed on to others.
• Infection – occurs when an infectious agent enters the body and begins to reproduce; may
or may not lead to disease.
• Pathogen – an infectious agent that causes disease.
• Host – an organism infected by another organism.
• Virulence – the relative ability of an agent to cause rapid and severe disease in a host.
Infectious diseases – present status
• Despite the availability and use of effective vaccines and antibiotics, infectious diseases
remain an important health problem worldwide.
• Infectious diseases are particularly important causes of death among the elderly, people
with acquired immunodeficiency syndrome (AIDS), those with chronic diseases, and those
receiving immunosuppressive drugs.
• In developing countries, unsanitary living conditions and malnutrition contribute to a
massive burden of infectious diseases that kills more than 10 million people each year.
• Most of these deaths are among children, especially from respiratory and diarrheal
Transmission of Infectious Diseases
Agents that cause infectious diseases can be transmitted in many ways.
• Through the air
• Through contaminated food or water
• Through body fluids
• By direct contact with contaminated objects
• By animal vectors such as insects, birds, bats, etc.
How Infectious Agents Cause Disease
• Production of poisons, such as toxins and enzymes, that destroy cells and
• Direct invasion and destruction of host cells.
• Triggering responses from the host’s immune system leading to disease
signs and symptoms.
• Derangement of normal physiological functions of organs or organelles.
Phases of infectious diseases
• Incubation period – time between infection and the appearance of signs and
• Prodromal phase – mild, nonspecific symptoms that signal onset of some diseases.
• Clinical phase – a person experiences typical signs and symptoms of disease.
• Decline phase - subsidence of symptoms.
• Recovery phase – symptoms have disappeared, tissues heal, and the body regains
Classification of infectious diseases
• Acute – develops and runs its course quickly.
• Chronic – develops more slowly and is usually less severe, but may persist for a long,
indefinite period of time.
• Latent – characterized by periods of no symptoms between outbreaks of illness.
• Local – confined to a specific area of the body.
• Systemic – a generalized illness that infects most of the body with pathogens distributed
widely in tissues.
• Primary – initial infection in a previously healthy person.
• Secondary – infection that occurs in a person weakened by a primary infection.
• Prions are composed of abnormal forms of a host protein, termed prion protein (PrP).
• These agents cause transmissible spongiform encephalopathies, including kuru (associated
with human cannibalism), Creutzfeldt-Jakob disease (CJD), bovine spongiform
encephalopathy (BSE; better known as mad cow disease), and variant Creutzfeldt-Jakob
disease (vCJD; probably transmitted to humans from BSE-infected cattle).
• PrP is normally found in neurons.
• Diseases occur when the PrP undergoes a conformational change that confers resistance to
• The protease-resistant PrP promotes conversion of the normal protease-sensitive PrP to
the abnormal form, explaining the infectious nature of these diseases.
• Accumulation of abnormal PrP leads to neuronal damage and distinctive spongiform
pathologic changes in the brain.
• Spontaneous or inherited mutations in PrP, which make PrP resistant to proteases, have
been observed in the sporadic and familial forms of CJD, respectively. CJD can be
transmitted from person to person iatrogenically, by surgery, organ transplant, or blood
• Viruses are obligate intracellular parasites that depend on the host cell's metabolic
machinery for their replication.
• They consist of a nucleic acid genome surrounded by a protein coat (called a capsid) that is
sometimes encased in a lipid membrane.
• Viruses are classified by their nucleic acid genome (DNA or RNA but not both), the shape of
the capsid (icosahedral or helical), the presence or absence of a lipid envelope, their mode
of replication, the preferred cell type for replication (called tropism), or the type of
• Because viruses are only 20 to 300 nm in size, they are best visualized with the electron
• Some viral particles aggregate within the cells they infect and form characteristic inclusion
bodies, which may be seen with the light microscope and are useful for diagnosis.
• Cytomegalovirus (CMV)-infected cells are enlarged and show a large eosinophilic nuclear
inclusion and smaller basophilic cytoplasmic inclusions; herpes viruses form a large nuclear
inclusion surrounded by a clear halo; and both smallpox and rabies viruses form
characteristic cytoplasmic inclusions. Many viruses do not produce inclusions (e.g., Epstein-
Barr virus [EBV]).
HIV-1 virions can be
seen on surface of
The variety of viral structures,
as seen by electron
A, Adenovirus, an icosahedral
nonenveloped DNA virus with
B, Epstein-Barr virus, an
icosahedral enveloped DNA
C, Rotavirus, a nonenveloped,
wheel-like, RNA virus.
D, Paramyxovirus, a spherical
enveloped RNA virus. RNA is
seen spilling out of the
• Most bacteria are bound by a cell wall consisting of peptidoglycan, a polymer of long sugar
chains linked by peptide bridges.
• There are two forms of cell wall structures: a thick wall surrounding the cell membrane that
retains crystal-violet stain (gram-positive bacteria) or a thin cell wall sandwiched between
two phospholipid bilayer membranes (gram-negative bacteria).
• Bacteria are classified by Gram staining (positive or negative), shape (spherical ones are
cocci; rod-shaped ones are bacilli), and need for oxygen (aerobic or anaerobic).
• Many bacteria have flagella, long helical filaments extending from the cell surface that
enable bacteria to move.
• Some bacteria possess pili, another kind of surface projection that can attach bacteria to
host cells or extracellular matrix.
• Most bacteria synthesize their own DNA, RNA, and proteins, but they depend on the host
for favorable growth conditions.
the surface of
The variety of bacterial morphology. The bacteria are
indicated by arrows in each panel. A, Gram stain of
sputum from a patient with pneumonia. There are
gram-positive cocci in clusters (Staphylococcus
aureus) with degenerating neutrophils. B, Gram stain
of sputum from a patient with pneumonia. Gram-positive,
elongated cocci in pairs and short chains
(Streptococcus pneumoniae) and a neutrophil are
seen. C, Gram stain of Clostridium sordellii grown in
culture. A mixture of gram-positive and gram-negative
rods, many of which have subterminal
spores (clear areas), are present. Clostridia species
often stain as both gram-positive and gram-negative,
although they are true gram-positive bacteria. D,
Gram stain of a bronchoalveolar lavage specimen
showing gram-negative intracellular rods typical of
Enterobacteriaceae such as Klebsiella pneumoniae or
Escherichia coli. E, Gram stain of urethral discharge
from a patient with gonorrhea. Many gram-negative
diplococci (Neisseria gonorrhoeae) are present within
a neutrophil. F, Silver stain of brain tissue from a
patient with Lyme disease meningoencephalitis. Two
helical spirochetes (Borrelia burgdorferi) are indicated
by arrows. The panels are at different magnifications.
• Fungi are eukaryotes that possess thick chitin-containing cell walls and ergosterol-containing
• Fungi can grow either as rounded yeast cells or as slender filamentous hyphae.
Hyphae may be septate (with cell walls separating individual cells) or aseptate,
which is an important distinguishing characteristic in clinical material.
• Some of the most important pathogenic fungi exhibit thermal dimorphism; that is,
they grow as hyphal forms at room temperature but as yeast forms at body
• Fungi may produce sexual spores or, more commonly, asexual spores referred to as
conidia. The latter are produced on specialized structures or fruiting bodies arising
along the hyphal filament.
• Fungi may cause superficial or deep infections.
• Superficial infections involve the skin, hair, and nails. Fungal species that are confined to
superficial layers of the human skin are known as dermatophytes. These infections are
commonly referred to by the term “tinea” followed by the area of the body affected (e.g., tinea
pedis, “athlete's foot”; tinea capitis, “ringworm of the scalp”). Certain fungal species invade the
subcutaneous tissue, causing abscesses or granulomas (e.g., sporotrichosis and tropical
• Deep fungal infections can spread systemically and invade tissues, destroying vital organs in
immunocompromised hosts, but usually heal or remain latent in otherwise normal hosts.
• Some deep fungal species are limited to a particular geographic region (e.g., Coccidioides in the
south-western United States and Histoplasma in the Ohio River Valley).
• Opportunistic fungi (e.g., Candida, Aspergillus, Mucor, and Cryptococcus), by contrast, are
ubiquitous organisms that either colonize individuals or are encountered from environmental
• In immunodeficient individuals, opportunistic fungi give rise to life-threatening infections
characterized by tissue necrosis, hemorrhage, and vascular occlusion, with little or no
inflammatory response. AIDS patients are often infected by the opportunistic fungus
Pneumocystis jiroveci (previously called Pneumocystis carinii).
• Parasitic protozoa are single-celled eukaryotes.
• Protozoa can replicate intracellularly within a variety of cells (e.g., Plasmodium in red blood
cells, Leishmania in macrophages) or extracellularly in the urogenital system, intestine, or
• Trichomonas vaginalis are flagellated protozoal parasites that are sexually transmitted and
can colonize the vagina and male urethra.
• The most prevalent intestinal protozoans, Entamoeba histolytica and Giardia lamblia, have
two forms: (1) motile trophozoites that attach to the intestinal epithelial wall and may
invade, and (2) immobile cysts that are resistant to stomach acids and are infectious when
• Blood-borne protozoa (e.g., Plasmodium, Trypanosoma, and Leishmania) are transmitted
by insect vectors, in which they replicate before being passed to new human hosts.
• Intestinal protozoa are acquired by ingestion of cysts from contaminated food or water.
• Toxoplasma gondii is acquired either by contact with oocyst-shedding kittens or by eating
cyst-ridden, undercooked meat.
• Parasitic worms are highly differentiated multicellular organisms.
• Their life cycles are complex; most alternate between sexual reproduction in
the definitive host and asexual multiplication in an intermediary host or
• Thus, depending on parasite species, humans could harbour adult worms
(e.g., Ascaris lumbricoides) or immature stages (e.g., Toxocara canis) or
asexual larval forms (e.g., Echinococcus species).
• Once adult worms take up residence in humans, they do not multiply but
they produce eggs or larvae that are usually passed out in stool.
• Often, the severity of disease is in proportion to the number of organisms
that have infected the individual.
• In some helminthic infections, disease is caused by inflammatory responses
to the eggs or larvae rather than to the adults (e.g., schistosomiasis).
• Ectoparasites are insects (lice, bedbugs, fleas) or arachnids (mites, ticks, spiders)
that attach to and live on or in the skin.
• Arthropods may produce disease directly by damaging the human host or
indirectly by serving as the vectors for transmission of an infectious agent into a
• Some arthropods cause itching and excoriations (e.g., pediculosis caused by lice
attached to hair shafts, or scabies caused by mites burrowing into the stratum
• At the site of the bite, mouth parts may be found associated with a mixed infiltrate
of lymphocytes, macrophages, and eosinophils.
• Arthropods can be vectors for other pathogens. For example, deer ticks transmit
the Lyme disease spirochete Borrelia burgdorferi
DIAGNOSING INFECTIOUS AGENTS
• Some infectious agents or their products can be directly observed in
hematoxylin and eosin–stained sections .
• Many infectious agents are best visualized by special stains that identify
organisms on the basis of particular characteristics of their cell wall or coat—
Gram, acid-fast, silver, mucicarmine, and Giemsa stains—or after labeling
with specific antibody probes.
• Regardless of the staining technique, organisms are usually best visualized
at the advancing edge of a lesion rather than at its center, particularly if
there is necrosis.
Techniques Infectious Agents
Gram stain Most bacteria
Acid-fast stain Mycobacteria, nocardiae (modified)
Silver stains Fungi, legionellae, pneumocystis
Periodic acid–Schiff Fungi, amebae
Giemsa Campylobacteria, leishmaniae, malaria
Antibody probes All classes
Culture All classes
DNA probes All classes
Serological and nucleic acid detection tests
• Acute infections can be diagnosed serologically by detecting pathogen-specific
antibodies in the serum.
• Nucleic acid–based tests.
• Nucleic acid amplification tests, such as polymerase chain reaction (PCR)
and transcription-mediated amplification, have become routine for
diagnosis of gonorrhea, chlamydial infection, tuberculosis, and herpes
Health ecosystem and emergence of new infectious
• Human demographics and behaviour are among the many variables that
contribute to the emergence of infectious diseases.
• Reforestation of the eastern United States has led to massive increases in the
populations of deer and mice, which carry the ticks that transmit Lyme disease,
Babesiosis, and ehrlichiosis.
• Failure of DDT to control the mosquitoes that transmit malaria and the
development of drug-resistant parasites have dramatically increased the morbidity
and mortality of Plasmodium falciparum in Asia, Africa, and Latin America.
• Microbial adaptation to widespread antibiotic use contributed to the emergence of
drug resistance in many species of bacteria, including Mycobacterium tuberculosis,
Neisseria gonorrhoeae, Staphylococcus aureus, and Enterococcus faecium.
• Infections with antibiotic-resistant bacteria are becoming a serious problem, such
as methicillin-resistant staphylococcus.
Emerging and newly discovered infectious
• Surprising number of new infectious agents continue to be discovered.
• The infectious causes of some diseases with significant morbidity and mortality were previously
unrecognized, because some of the infectious agents are difficult to culture; examples include Helicobacter
pylori gastritis, HBV and HCV, and Legionnaires pneumonia.
• Some infectious agents are genuinely new to humans, e.g., HIV, which causes AIDS, and B. burgdorferi,
which causes Lyme disease.
• Other infections have become much more common because of immunosuppression caused by AIDS or
therapy for transplant rejection and some cancers.
• Infectious diseases that are common in one area may be introduced into a new area. For example, West
Nile virus has been common in Europe, Asia, and Africa for years but was first described in the United States
Recognized Infectious Agent Manifestations
1977 Ebola virus Epidemic Ebola hemorrhagic fever
Hantaan virus Hemorrhagic fever with renal syndrome
Legionella pneumophila Legionnaires disease
Campylobacter jejuni Enteritis
1980 HTLV-I T-cell lymphoma or leukemia, HTLV-associated myelopathy
1981 Staphylococcus aureus Toxic shock syndrome
1982 Escherichia coli O157:H7 Hemorrhagic colitis, hemolytic-uremic syndrome
Borrelia burgdorferi Lyme disease
1983 HIV AIDS
Helicobacter pylori Gastric ulcers
1988 Hepatitis E Enterically transmitted hepatitis
1989 Hepatitis C Hepatitis C
1992 Vibrio cholerae O139 New epidemic cholera strain
Bartonella henselae Cat-scratch disease
1995 KSHV (HHV-8) Kaposi sarcoma in AIDS
1999 West Nile virus West Nile fever, neuroinvasive disease
2003 SARS coronavirus Severe acute respiratory syndrome
AGENTS OF BIOTERRORISM
Category A Diseases/Agents
Anthrax (Bacillus anthracis)
Plague (Yersinia pestis)
Smallpox (Variola major
Viral hemorrhagic fevers
(filoviruses [e.g., Ebola,
Marburg] and arenaviruses
[e.g., Lassa, Machupo])
Category C Diseases/Agents
Emerging infectious disease
threats such as Nipah virus and
Category B Diseases/Agents
Brucellosis (Brucella sp.)
Epsilon toxin of Clostridium perfringens
Food safety threats (e.g., Salmonella sp.,
Escherichia coli O157:H7, Shigella)
Glanders (Burkholderia mallei)
Melioidosis (Burkholderia pseudomallei)
Psittacosis (Chlamydia psittaci)
Q fever (Coxiella burnetti)
Ricin toxin from Ricinus communis (castor
Staphylococcal enterotoxin B
Typhus fever (Rickettsia prowazekii)
Viral encephalitis (alphaviruses [e.g.,
Venezuelan equine encephalitis, eastern
equine encephalitis, western equine
Water safety threats (e.g., Vibrio cholerae,
TRANSMISSION AND DISSEMINATION OF
• Microbes can enter the host by inhalation, ingestion, sexual transmission,
insect or animal bites, or injection.
• The first defenses against infection are intact skin and mucosal surfaces,
which provide physical barriers and produce antimicrobial substances.
• In general, respiratory, gastrointestinal, or genitourinary tract infections
that occur in healthy persons are caused by relatively virulent
microorganisms that are capable of damaging or penetrating intact
• In contrast, most skin infections in healthy persons are caused by less
virulent organisms entering the skin through damaged sites (cuts and
HOW MICROORGANISMS CAUSE DISEASE
• They can contact or enter host cells and directly cause cell death.
• They may release toxins that kill cells at a distance, release enzymes that
degrade tissue components, or damage blood vessels and cause ischemic
• They can induce host immune responses that, though directed against the
invader, cause additional tissue damage.
• They are necessary to overcome the infection but at the same time may
directly contribute to tissue damage.
Mechanisms of Viral Injury
• Viruses can directly damage host cells by entering them and replicating at
the host's expense.
• The predilection for viruses to infect certain cells and not others is called
tropism and is determined by several factors, including
(1)expression of host cell receptors for the virus,
(2)presence of cellular transcription factors that recognize viral enhancer and
(4)local temperature, pH, and host defences.
Mechanisms of Bacterial Injury
• Bacterial Virulence.
• Bacterial Adherence to Host Cells.
• Virulence of Intracellular Bacteria.
• Bacterial Toxins.
• Injurious Effects of Host Immunity
IMMUNE EVASION BY MICROBES
• Microorganisms have developed many means to resist and evade the
(1)growth in niches that are inaccessible to the host immune system,
(3)resistance to innate immune defenses, and
(4)impairment of effective T-cell antimicrobial responses by specific or
Mechanisms of Antigenic Variation
Type Example Disease
High mutation rate HIV AIDS
Influenza virus Influenza
Genetic reassortment Influenza virus Influenza
(e.g., gene recombination,
gene conversion, site-specific
Borrelia burgdorferi Lyme disease
Neisseria gonorrhoeae Gonorrhea
Trypanosoma sp. African sleeping sickness
Plasmodium sp. Malaria
Large diversity of serotypes Rhinoviruses Colds
Streptococcus pneumoniae Pneumonia
SPECTRUM OF INFLAMMATORY RESPONSES TO
• Suppurative or purulent inflammation.
• Mononuclear and granulomatous inflammation
• Cytopathic or cytoproliferative reaction.
• Tissue necrosis
• Chronic inflammation and scarring.
• This pattern is the reaction to acute tissue damage is characterized by increased vascular
permeability and leukocytic infiltration, predominantly of neutrophils.
• The neutrophils are attracted to the site of infection by release of chemoattractants from the
“pyogenic” (pus-forming) bacteria that evoke this response, mostly extracellular gram-positive
cocci and gram-negative rods.
• Massing of neutrophils and liquefactive necrosis of the tissue form pus.
• The sizes of exudative lesions range from tiny microabscesses formed in multiple organs during
bacterial sepsis secondary to a colonized heart valve to diffuse involvement of entire lobes of the
lung in pneumonia.
• How destructive the lesions are depends on their location and the organism involved.
• Pneumococci usually spare alveolar walls and cause lobar pneumonia that resolves completely,
whereas staphylococci and Klebsiella species destroy alveolar walls and form abscesses that heal
with scar formation.
• Bacterial pharyngitis resolves without sequelae, whereas untreated acute bacterial
inflammation of a joint can destroy it in a few days.
Mononuclear and Granulomatous Inflammation
• Diffuse, predominantly mononuclear, interstitial infiltrates are a common feature
of all chronic inflammatory processes.
• They often are a response to viruses, intracellular bacteria, or intracellular
parasites. In addition, spirochetes and helminths provoke chronic inflammatory
• Which mononuclear cell predominates within the inflammatory lesion depends on
the host immune response to the organism.
• Granulomatous inflammation is a distinctive form of mononuclear inflammation
usually evoked by infectious agents that resist eradication and are capable of
stimulating strong T cell–mediated immunity
• Granulomatous inflammation is characterized by accumulation of activated
macrophages called “epithelioid” cells, which may fuse to form giant cells. In some
cases there is a central area of caseous necrosis.
• The lesions are characterized by cell necrosis or
cellular proliferation, usually with sparse
• Some viruses replicate within cells and make viral
aggregates that are visible as inclusion bodies
(e.g., herpesviruses or adenovirus) or induce cells
to fuse and form multinucleated cells called
polykaryons (e.g., measles virus or
• Focal cell damage in the skin may cause epithelial
cells to become detached, forming blisters
• Some viruses can cause epithelial cells to
proliferate (e.g., venereal warts caused by HPV or
the umbilicated papules of molluscum
contagiosum caused by poxviruses).
• Finally, viruses can contribute to the
development of malignant neoplasms.
• Clostridium perfringens and other organisms that secrete powerful toxins can
cause such rapid and severe necrosis (gangrenous necrosis) that tissue damage is
the dominant feature.
• Because few inflammatory cells are present, these lesions resemble infarcts with
disruption or loss of basophilic nuclear staining and preservation of cellular
• Clostridia are often opportunistic pathogens that are introduced into muscle tissue
by penetrating trauma or infection of the bowel in a neutropenic host.
• Similarly, the parasite E. histolytica causes colonic ulcers and liver abscesses
characterized by extensive tissue destruction with liquefactive necrosis and
without a prominent inflammatory infiltrate.
• By entirely different mechanisms, viruses can cause widespread and severe
necrosis of host cells associated with inflammation, as exemplified by total
destruction of the temporal lobes of the brain by herpesvirus or the liver by HBV.
Chronic Inflammation and Scarring
• Chronic HBV infection may cause cirrhosis of
the liver, in which dense fibrous septae
surround nodules of regenerating hepatocytes.
• Sometimes the exuberant scarring response is
the major cause of dysfunction.
• “pipe-stem” fibrosis of the liver or fibrosis of
the bladder wall caused by schistosomal eggs
or the constrictive fibrous pericarditis in