Mary Melati is a sophomore at Cornell University studying biological sciences.
The relationship between Gram-positive bacterium Streptococcus pyogenes (Group A Streptococcus; GAS) and the human host is the leading cause of human acute bacterial pharyngitis, more commonly known as strep throat.
GAS follows a general bacterial disease cycle, which includes transmission, attachment, infection, colonization, and reproduction. GAS transmission can happen directly between hosts. Humans are the largest maintenance population of GAS. In fact, one quarter of all people who experience sore throat (1/3 of them school-aged children) have GAS pharyngitis (Danchin et al., 2007). The advent of child care, which concentrates many children in one place, also leads to higher rates of GAS transmission in young children (Danchin et al., 2007). Moreover, individuals are twice more likely to have a secondary case of GAS pharyngitis from a family member than from a primary case in the community (Danchin et al., 2007). In other words, GAS bacteria can spread widely from normal human interaction. Unhygienic habits such as coughing or sneezing without covering the mouth or using a disposable tissue can also lead to greater spread of the pathogen indirectly through the environment. Because GAS can grow to a high density in saliva, its chances of transmission to new hosts are high, especially since host mouth-and-hand and hand-and-surrounding interactions occur so frequently each day (Tart et al., 2007). Bar-Dayan et al. (1997) found that food-borne transmissions can also happen. Once it enters the host, GAS targets host immune defense mechanisms and attach to the host pharynx, or throat. Having survived entry into the human host, GAS then proceeds to invade the host cells to maximize its fitness and adapt to the host environment. GAS proliferates in the host pharynx, where saliva contains a rich medium that supports bacterial growth. In this way, GAS has a long-lasting and persistent infection and successful colonization in human hosts.
The host body actively retaliates the GAS infection with a slew of internal changes aimed at disrupting the pathogen’s environment. However, GAS overcomes these changes through rapid and extensive remodeling of its transcriptome, or all the RNA molecules expressed from its genome. Graham et al. (2005) found that within 30 minutes after being placed in human blood ex vivo, GAS had upregulated 716 and downregulated 425 gene transcripts. This finding highlights the aptitude of GAS to adjust and proliferate in different host environments. GAS can even regulate their levels of virulence, or ability to cause disease, to balance with its host. GAS virulence factors are all directed towards overcoming innate host defenses and cause severe cellular damage. However, it may be detrimental for the bacteria to cause so much damage that the host dies before the pathogen can transmit to another host. Hence, in a vital evolutionary tradeoff, GAS must regulate the transcription of its virulence factors in order to maximize its life and persist long enough in the host to disperse to other hosts.
GAS does not only change its virulence factors to modulate its ability to make the human host sick, but also its serotypes, or characteristic bacterial features that induce a host immune response. Virtaneva et al. (2003) showed that in one patient infected with two strains of serotypes, differences are present even in the transcript level, making it difficult to predict and treat against specific strains of GAS. There is also a continuous pouring in of new serotypes from the environment, which ultimately leads to random genetic drift that also makes it difficult for host immune responses to detect GAS.
Studies on GAS antibiotic resistance reveal a bleak answer to why GAS is difficult to treat. Internalization of GAS within host cells enables the pathogen to evade host defenses and offers protection against antibiotics such as penicillin, which does not enter cells (Tart et al., 2007). Moreover, antibiotics could fail because GAS bacteria can survive intracellularly for days before the host cell dies, which means GAS can persist in the host for longer than the prescribed dosage of antibiotics (Courtney et al., 2002). A Wake Forest School of Medicine study also suggested high asymptomatic streptococcal carriage in pediatric patients, which highlights the difficulty of knowing when to isolate a patient carrying the pathogen since it is difficult to detect the presence of GAS in the first place (Roberts et al., 2012). It is clear that GAS bacteria is opportunistic and can easily evade human immune responses.
This situation calls for an effective management plan in the future. First, there must be effective detection of the pathogen. Then a doctor may prescribe an antibiotic schedule. But to deal with antibiotic resistance and antigenic variation trends, this disease management plan will also look at other strategies, such as immune and non-immune mediated killing of pathogen and management outside the body.
Detection. A quicker detection of GAS in infected individuals can lead to an earlier administration of medical treatment, which will consequently lead to less chance of spread to other individuals. This strategy is important on a temporal scale because it shortens the period during which an infected individual can spread the pathogen to another person and can decrease the unnecessary prescription of antibiotics. In other words, this management strategy will target the earlier stages of the GAS disease cycle in an attempt to treat it quickly and effectively before GAS colonizes the host.
Current detection techniques include using rapid strep tests and throat cultures (McIsaac et al., 2004). Rapid strep tests entail the patient’s throat being swabbed for a sample of mucus. Then, the sample is applied to a nitrocellulose film on which GAS antigens would bind with antibodies and induce a visible color change, signaling a positive result for GAS (Cohen et al., 2013). On the other hand, throat cultures also entail the patient’s throat being swabbed, but the sample is then cultured in lab for two days to see the presence and growth of GAS bacteria. While the throat culture method is generally more accurate and sensitive, the rapid testing without confirmatory cultures is more cost effective (McIsaac et al., 2004).
Antibiotics. Antibiotics are originally derived from soil bacteria and have been molded for human benefit to kill off other competing bacteria in human systems. Though antibiotics can be highly effective against GAS pathogens, they must still be avoided because of ever increasing drug-resistant GAS strains.
Using antibiotics to eradicate GAS pathogen is efficient and relative low cost. It can also be crucial in a spatial scale, since the more GAS bacteria get degraded in a host system by the antibiotics, the smaller chance it has of proliferating. Shulman et al. (2012) noted that patients with GAS-induced diseases should be treated with appropriate antibiotics at an appropriate dose for a duration of about 10 days to eradicate the pathogen from the pharynx. The recommended drugs against GAS bacteria are penicillin, amoxicillin, or cephalosporin. Unlike with many other bacteria, a pencillin-resistant GAS has never been documented (Shulman et al., 2012). On the other hand, tetracyclines (antimicrobials) should not be used because of high prevalence of resistant strains (Shulman et al., 2012). If patients are allergic to penicillin, macrolides are often prescribed. However, frequent use of macrolides leads to GAS resistance, so in the past years, use of macrolides prescription in pediatric population has decreased (Gagliotti et al., 2015).
Because of the generally increasing number of resistant strains of bacteria, it is important to use less and less antibiotics and look at alternative strategies to manage the GAS pathogen-induced diseases. Interestingly, better rapid strep tests can allow family doctors to persuade patients that negative rapid test results (hence, perhaps a viral infection) means antibiotics are not required (Worrall et al., 2007). Contrary to popular belief, symptoms caused by bacterial sore throat do not go away faster with antibiotics than if they were untreated. This issue raises questions about whether doctors should be prescribing antibiotics for strep throat at all. Doctors are not necessarily the only antagonists in this situation, since patients also pressure doctors to give them unnecessary antibiotic prescriptions because that is what they expect. A solution to this problem could be to better educate the public about antibiotics so that antibiotics usage keeps decreasing, an effort the CDC and other public health organizations are currently working very hard to address.
Vaccines and the Body. One alternative solution to prevent the prescription of antibiotics is the vaccine. Vaccines work by exposing the individual to some part of the pathogen so that the host immune system can create antibodies to detect that pathogen in the future and thus effectively and quickly protect the body from the pathogen. Effective vaccination can avoid the need of medicine for GAS-induced diseases altogether, because the individual host will be well-prepared to combat the pathogen. Some obstacles to this strategy could be its acceptance and its availability to all members of the population. Recently, there is a focus for an M-protein based vaccine because M-protein is a variable, multi-functional adhesive GAS protein with the ability to bind to many host plasma proteins (Batzloff et al., 2004). Increasing host antibodies which can detect GAS virulence factors like M-protein will lead to quicker eradication of GAS and less disease. Ji et al. (1997) also found that intranasal immunization produced significant mucosal and systematic antibody responses that could detect and eliminate the foreign substance faster and faster each time it is administered. Perhaps nasal or oral vaccines are more effective than injections so that the mild virulence factors travel directly to the typical site of infection for a faster host response. Batzloff et al. (2004) argue that a greater library of antigens and protective mechanisms should be mandatory and pursued for long-lasting efficacious GAS vaccine strategy. Moreover, Brandt et al. (2000) found that vaccines should be administered early in childhood to lead to greater adulthood immunity and enhanced detection of the pathogens.
Bacteriophages. An alternative method of controlling GAS is using commensal bacteria already in the body to compete with GAS. A strength of this method is that it is more natural and avoids the use of antibiotics. Batzloff et al. (2004) found that some commensal bacteria secrete inhibitory substances that work against GAS colonization. Perhaps infusion of large numbers of other commensal bacteria to the body can also work to control GAS by commensal bacteria outcompeting GAS bacteria in the throat so that GAS cannot proliferate. However, a possible problem with this method is that introducing new bacteria to the body may cause an imbalance in the microbiome and cause other diseases. A way to avoid this is to infuse more of the commensal bacteria already inside the body in equal ratio to the normal conditions. Furthermore, bacteriophages, viruses that parasitizes bacteria by infecting it and reproducing inside it, can be used to manage GAS. There seems to be little research done on bacteriophages in the last decade, but in the past Fischetti and Zabriskie (1968) found that GAS bacteriophages absorb into GAS cell walls effectively and irreversibly. In other words, bacteriophages could work commensally with the body to degrade GAS in the pharynx very quickly.
Surgery. Another idea is to physically remove infected tissue. Pus can be drained from the infection or use surgical procedures to remove all infected cells so that GAS cannot spread (Steer et al., 2012). However, this method receives a lot of criticism because it is neither time nor cost efficient and seems unnecessary especially with the effective drugs currently available.
Outside the Body. So far the focus has been on the biological aspects of management inside the body. However, the host environment is also important to consider in managing the disease because it can lead to prevention of GAS infection. First, all cases of suspected infection should be identified and notified to local health protection specialists (Steer et al., 2012). This is important so that infected individuals can be treated sooner and avoid spreading the pathogen to others, especially since every day places are very interactive. Along the same lines, when there is a breakout of strep throat, there should be additional throat screening of individuals (Ridgway & Allen, 1993). This is to ensure that the pathogen spread is cut short and those infected can be let known as soon as possible so that they know to avoid other individuals until they have recovered. In addition, patients with GAS should be placed in isolation for a minimum of 24 hours until the throat cultures show negative or their rapid strep tests no longer detect the presence of GAS (Steer et al., 2012). Environmental contamination of everyday objects may also provide a source of infection of patients (Ridgway & Allen, 1993). Thus, environmental cleaning and hand washing should be more regulated to prevent spread by touching every-day objects (Steer et al., 2012; Ridgway & Allen, 1993). This is one of the most useful preventive measures with any infectious disease.
There are many aspects of GAS infection biology that need to be considered for a disease management plan against strep throat. The bacteria can be managed before it even begins its disease cycle by properly controlling the host environment, which includes hand-washing and isolating infected humans to prevent transmission. Though the human body is well equipped and prepared to combat infection, GAS bacteria can easily adapt its gene expression to better cope with the unfavorable host environment. The use of antibiotics should be discouraged because it could lead to GAS antibiotic resistance. This is what led to the idea that competition from other bacteria could manage GAS pathogen in the throat led researches to explore bacteria phages as a way of management. Though it is still an under-written topic, investment in research regarding this could lead to rewarding results for an alternative form of disease management. Other current strategies of managing GAS disease includes strengthening immune mediated killing of the pathogen, such as by using vaccines. New vaccines can be effective, though it may be very expensive to develop and difficult to keep updated with increasing GAS antigenic variation.
This management plan can also be used for similar bacterial infections, such as Bordetella pertussis, which causes whooping cough. With existing opportunities to use various developing methods to manage GAS, GAS-induced diseases can one day be controlled effectively.