Lecture 2- airborne infections Flashcards
what is the human respiratory tract?
site of entry and exit for pathogens
pathogens easily transmitted in droplets
Breathe, talk, cough, sneeze
Normal bacterial flora
Many are opportunist pathogens
Neiserria meningitidis
Haemophilus influenzae
Streptococcus pneumoniae
Airborne transmission of pathogens
Many microorganisms in droplets are inactivated by rapid drying or light,
close contact is needed for transmission - influenza virus, meningococcus
Others are more hardy and survive much longer in air or in dust
- Corynebacterium, Mycobacterium
what is respiratory syncytial virus?
Viral infection of lower respiratory tract - bronchiolitis
Significant impact in children less than 1.
>.6 months
Peak 2-3 months
Premature babies esp vulnerable
Death up to 11,000 children per year
Seasonal
Symptoms begin 3-7 days after exposure
Include runny nose, fever, cough, rhinitis, wheezing, difficulty breathing
Progress to bronchitis and viral pneumonia
what is the organism and pathogenesis of respiratory syncytial virus
The organism -
Member of paramyxovidiae family
Negative strand RNA virus
Enveloped virus
Varies in size and shape
Pathogenesis -
Two viral proteins associated disease
G protein binds the virus to the host cell
F protein allows fusion of host cell membranes
Formation of multinuclear or ‘syncytic’ cells
what is Diphtheria (Corynebacterium diphtheriae)?
In Europe considered an ‘ancient disease’
As late as 1950’s major cause of death
Largely controlled by vaccination
Still common in some poor urban communities, 10-15% mortality, approx 5000 deaths p.a., mainly in children <5 years
Problem displaced populations
what organism causes Diphtheria (Corynebacterium diphtheriae)?
non-sporulating, aerobic Gram-positive bacillus
humans are only known reservoir
grows in the upper respiratory tract, usually throat,
sometimes without harm to the host (carrier state )
extracellular and does not invade the tissues
Cells of C. diphtheriae showing typical club shaped appearance (not spore related)
what is Toxin mediated disease (diphtheria toxin)?
Production of toxin locally
Death of cells
Subsequent inflammatory response
Production of leathery pseudo-membrane of bacterial cells, dead inflammatory cells and fibrin
Obstruction of the airway
Pseudomembrane in an active case of diphtheria
Interestingly, the gene encoding the toxin is carried by a lysogenic phage which has become integrated into the bacteria chromosome. Carriage of this phage is a great example of how bacteriophages play a role in acquisition and spread of new virulence traits in bacteria.
The toxin itself is synthesized as a single polypeptide of 535 aa that includes the B domain at the carboxy terminal – important for binding the toxin to the cell
And an A or active domain which contains an enzyme encoding ADP ribosylating activity.
The toxin works by binding via the B domain to the cell, stimulating its uptake by endocytosis.
Within the endocytic vesicle, it undergoes proteolytic cleavage and disulphide bonds linking the two parts of the protein are reduced releasing the A subunit into the cytosol of the cell
There it is able to modify the eukaryotic elongation factor (EF-2), a key protein in protein translation.
In this inactivated form, protein translation in the cell is halted and the cell dies. Obviously, if the toxin acts on cardiac cells or those of the nervous system – death can result.
what is the pathogenesis of diphtheria??
However, management of a pseudomembrane, which is not found in all infections, is not the main consideration with respect to disease outcome. More significant is the fact that toxin produced by organisms can dissemination into the blood, causing toxemia and widespread damage to organs including the heart, kidneys and nervous system
Other factors that enhance pathogenesis
(evade host immune response)
Express Diphthin - an IgA protease - cleaves IgA
Cord factor - trehalose dimycolate, a cell wall component toxic for eukaryotic cells
what is the treatment of diphtheria?
Treatment
(Horse) antitoxin - neutralises toxin
Antibiotics - must be given early
Penicillin, erythromycin
Vaccine
Component of Triple vaccine DTaP
formalin-treated diphtheria toxin (toxoid) (D) + tetanus toxoid (T) and pertussis acellular vaccine(aP)
Vaccination does not prevent carriage and organism persists in community,so vaccination must continue.
what is tuberculosis?
Now we know that people have been dying from TB for millions of years with descriptions of symptoms associated with untreated TB, including physical wasting, uncontrolled fits of coughing and the appearance of blood-stained sputum described in Eygptian hierogliphs
However, Mycobacterium tuberculosis wasn’t identified as the causative agent of TB until 1882; a time when 1 in 7 deaths were caused by this infection.
Since then, several factors have contributed to a significant reduction in infection rates including improvements in housing conditions, and diet, isolation of infected patients (in sanitariums), the introduction of antibiotics and more latterly the introduction of vaccination
is tuberculosis currently a problem?
However, the spread of HIV especially on the African content, displacement of human populations as a consequence of famine, international travel and homelessness and drug abuse have all contributed to a resurgence of infection that resulted in the WHO declaring in 1993 that the spread of TB was a global emergency.
In last 20 years – situation improved in some countries (US)
Most burden Asia, Africa and Western Pacific
1.6m deaths in 2021 HIV negative individuals up from 1.4m in 2019
what are diseases associated with inflammation of bronchioles?
Although the exact mechanism of disease is unclear, the cytotoxic injury caused to the lungs results in initiation of an inflammatory response that restricts the airways and limits gaseous exchange.
And yet cell mediated immunity is essential for clearance of the virus as children with poor cell mediated immunity continue to shed the virus.
Infection control
Virus spread via direct contact (poor environmental survival)
Patient isolation
Virus Inactivated water and soap
Treatment
Inhaled ribavirin in patients with severe bronchiolitis
RNA nucleoside inhibitor – interferes with replication
Prophylaxis for susceptible children
Monoclonal antibody – palinzumab binds to the G protein and inhibits its entry into cell
Vaccines
No licensed vaccine (until 2023)
First approach – formaldehyde fixed virus associated with enhanced disease
FDA approved 2 ‘vaccines’ in 2023
Passive immunisation of infants
Monoclonal antibody with extended life (nirsevimab)
To be given to infants up to 6 months especially during winter months
Recommended in pre-term babies
Reduce disease severity
Active vaccination of expectant mothers and over 65’s
Protein vaccine based on RSVpreF protein from 2 of the major antigenic subgroups A and B)
Generates antibodies that reduce infection (herd immunity)
Passively transferred mother to child
Protects baby from birth and for first few months of life
what is the pathogenesis of tuberculosis?
In terms of TB pathogenesis, following inhalation of the organism into the lungs the bacteria are taken up by macrophages.
The bacteria encode multiple different systems that interfer with the capacity of these macrophages to kill this internalized cargo which means instead of being killed, the bacteria can survive and multiply within the macrophages.
To limit the spread of these infected macrophages throughout the body, the host’s response is to restrict the infection to ‘tubercles’ which are small granulomas, in which epitheloid cells, giant cells and immune cells surround and wall off the infected macrophage
Subsequently many of these tubercles will heal spontaneously or become fibrotic or calcified, persisting for the rest of the life of the infected individual
However, in a small proportion of people with primary TB, the mycobacteria are not contained within the tubercle and can spread to the blood causing disseminated disease and death
Secondary TB can also occur if the dormant mycobacteria are reactivated after impairment of the immune system by factors such as malnutrition, infections and age. The subsequent breakdown of the tubercle allows the bacteria to spread to the blood and organs resulting in systemic disease and death
In advanced TB, lung tissue and function are destroyed by activated lesions
is exposure to TB a death sentence?
Well not necessarily of those that get exposed, approx. 70% will clear the infection with no further sequlae
Of the remaining 30%, approx. 5-10% will develop primary TB as a consequence of the immune systems failure to control the disease
Of the remaining 20-25%, 90-95% the infection will be contained effectively within the tubercles which although visible by Xray may not cause any issues.
The remaining 5% will develop secondary TB as a consequence of tubercle breakdown
how do you treat TB?
antibiotics
Prolonged treatment (6-18 months) with combinations of 4 drugs isoniazid, rifampicin, pyrazinamide and ethambutol
Emergence of resistant strains.
MDR-TB (multi-drug resistant) resistant to at least isoniazid and rifampicin, the two most powerful first-line drugs
what is Mycobacterium tuberculosis?
The organism
slow growing, non-sporing, aerobic, Gram-positive bacillus acquired by
inhalation, tubercle bacilli survive for long periods in air or dust
Pathogenesis
Damage is not due to a toxin but to host immune response trying to combat this persistent organism
Capacity to evade host immunity by invasion and persist in macrophages.
why is tuberculosis an ongoing and difficult problem?
needs to be controlled world-wide
A political as well as a medical problem
Requires better
surveillance (WHO)
diagnosis
drugs
vaccines
what are XDR strains of TB
More worrying is the emergence of extreme drug resistance (XDR) strains of TB which show resistance to both first line and second line antibiotic treatments and isolation of these strains have been described around the world including the UK
And it is only a matter of time before a fully resistance strain emerges
what are examples of Pulmonary and extra-pulmonary TB?
Whilst Mycobacterium tuberculosis is considered to be the commonest cause of TB, other Mycobacterial species can cause TB like illness. These includes M bovis, M microti and M africanum, which as the name implies is a major issue in Africa
Unlike diphtheria that remains largely an infection of the upper respiratory tracts, although TB is primarily a disease of the lungs, the bacteria can also disseminate via the blood to other sites within the body causing meningitis, infection of the bones and joints and the urogenital tract. This is known as extrapulmonary TB.
what is the examples of the BCG vaccines?
Live attenuated vaccine
BCG - Bacille Calmette-Guerin
Isolated in 1904 as an attenuated mutant of M. bovis
Used first as a TB vaccine in humans in 1921
Administered to over 3 billion humans to date
- Efficacy?
80% of world’s children vaccinated
Limit TB meningitis
Cheap and safe but level of protection is controversial
efficacy ranges from 80%- 0%
what is the human respiratory tract and its defence mechanisms?
Physically the respiratory surface is protected by a highly proficient filtering system if you consider that the average adult inhales around 6L of gas per min.
The size of the pathogen itself is very important in determining the depth within the respiratory tract these organisms can penetrate with particles greater 10um trapped in the upper respiratory tract , whilst those less than 5um are able to reach the alveoli sacs
The main mechanism of clearance is the mucocillary escalator, in which mucus, a mixture of glycoproteins, forms a blanket that coats the airway from the alveoli to the trachea.
Movement of ciliated cells, propel captured material, including dust, microorganisms and dust from the lower and upper respiratory surfaces to the back of the throat where it is swallowed.
This layer not only reduces the capacity of microbes to physically interact with the cells of the respiratory tract but also provides sugars that act as decoy receptors, binding pathogens and enhancing their removal
Activities such as smoking can reduce ciliary activity, leading to enhanced pathogen colonization. Interestingly the bacteria Bordetella pertussis that causes whooping cough, produces a specific tracheal cytotoxin which specifically destroys cilliated cells, to prevent removal of this pathogen.
Coughing is also an important cleansing function as this involves passing air at rapid speeds through the narrow airways results in the shearing and removal of mucus within the larger airways
The respiratory tract is also surrounded by several secondary lymphoid tissues that include the tonsils, cervical and tracheobronchial lymp nodes
what is alveolar macrophages, alveolar inflammatory responses and other factors
Alveolar macrophage
primary defence of the lungs
effector cells - phagocytic and microbicidal activities
antigen presenting cells – induction of acquired T-cell responses
Alveolar inflammatory (Innate) response
influx of neutrophils (phagocytic and microbicidal) into the alveoli (diapedesis)
in response to chemotactic factors such as complement to combat the infection
Other factors
Lung surfactant/antimicrobial peptides - may enhance bactericidal activity of macrophage and complement
Lysozyme - digests bacterial peptidoglycan
Transferrin and lactoferrin - bind available iron
Adaptive response
IgG - opsonins (promote phagocytosis)
Lymphoid tissue providing T and B cells for the immune response
