The role of P. acnes in the pathogenesis of acne vulgaris

Acne vulgaris continues to burden every generation, and despite the multitude of the treatments and products on the market, there is still no magic formula that can guarantee a long-term benefit to all acne patients. Antibiotics are most common treatment. However they cannot be given long term. Furthermore, widespread use of antibiotics is thought to be a factor in the rise of antibiotic-resistant bacteria, possibly leading to greater harm than benefit. Vitamin A derivatives (isotretinoins) represent the second widely used treatment option. Oral isotretinoin suppresses sebaceous gland activity and so indirectly reduces inflammatory lesions; nevertheless, isotretinoin is not a curative drug and discontinuation of the treatment is frequently followed by recurrence in the absence of appropriate maintenance treatment.1 Besides, due to potentially serious side effects (birth defects, vision problems, mental health problems, hair loss, vision problems, etc.), isotretinoin is not routinely prescribed to patients. Therefore, acne patients would welcome an alternative, safer, and long-term effective treatment. Devising an alternative prophylactic and curative treatment may soon be possible, thanks to the recent research findings that have uncovered the pathogenic role of the long-suspected culprit, a bacterium named Propionibacterium acnes (P. acnes).

Acne vulgaris affects >85% of teenagers and >10% of adults and has recently been re-defined as a complex chronic disease associated with P. acnes, which takes advantage of immune susceptible host.2–5 In the past, the pathogenic role of P. acnes has been debated due to the fact that this bacterium is found not only on the skin of acne patients, but also on the skin of healthy individuals. The theory that P. acnes does not cause the acne per se, but rather contributes to inflammation once the acne lesion has been formed, has been challenged by the newest epidemiological studies using highly sensitive, improved methods for genetic profiling.

These and other studies have uncovered important new facts about acne formation:

  • Significant differences between the P. acnes strains isolated from the patients with severe acne compared to healthy controls;4,6
  • Striking functional differences among strains from different phylogenetic clusters.7,8
  • P. acnes secretion of a glycocalyx biofilm that acts as an “adhesive glue” for the corneocytes, thereby inducing comedonal acne.9,10
  • Bacterial biofilms acting as a protective barrier to antibactericidal agents used in acne therapy.11,12

P. acnes resides on the surface of our skin and in the most individuals it poses no problem. In fact, it is even considered the “gate keeper”, protecting our skin from colonization by pathogens that can cause more severe infections. However, not all P. acnes strains are harmless skin protectors. Each of us carries a distinct population of P. acnes strains, and if we happen to be colonized by a more virulent type, the strain may take the advantage of the skin’s unique environment, and in the absence of effective immune defenses, spread to the deeper skin layers (dermis) where it will induce inflammation.

What factors facilitate the P. acnes invasion of deeper skin layers?
P. acnes colonizes and grows optimally in the presence of lipids and in the absence of oxygen. Sebum secretion is intensified during puberty and other hormonally active periods (e.g. premenstrual period or pregnancy). Increased sebum production provides an ideal environment for P. acnes and attracts the bacteria into the hair follicles, which are located deeper within the skin (Figure 1). Additional genetic factors may be also at play. However, regardless of the signal that attracts them, our immune system must be able to recognize the bacteria and rapidly eliminate them, in order to prevent the formation of acne lesions.

If the immune system is not effective enough, it can be trained to respond more efficiently through vaccination.

A vaccine against P. acnes could be designed to induce a stronger immune response against specifically targeted virulent P. acnes strains. Such a vaccine could provide the benefits that are not available from other types of therapies including the following:

  • Rapid and effective cure
  • Long-term protective effect
  • Preservation of normal bacterial skin flora
  • Does not contribute to antibiotic resistance of bacteria
  • Avoids unwanted side-effects, since the vaccine would induce the immune response against foreign, and not host cells
  • Prophylactic application would be also possible, before acne scars are formed
The role of P. acnes in the pathogenesis of acne vulgaris
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Figure 1. The role of P. acnes in acne pathogenesis.

  1. Sebum secretion and clogged pores limit access to oxygen.
  2. High lipid content and low oxygen concentration creates optimal growth environment for P. acnes.
  3. P. acnes residing on the skin surface is attracted to lipid-rich, optimal environment inside the hair follicles. Here, the bacteria rapidly multiply inducing a local inflammatory response. If the immune system is not able to efficiently kill and remove the bacteria, the inflammatory reaction persists leading to the creation of cysts and pustules, ultimately leading to the creation of scars.

REFERENCES

  1. Kurokawa, I. et al. New developments in our understanding of acne pathogenesis and treatment. Experimental dermatology 18, 821-32 (2009).
  2. Grange, P. a, Weill, B., Dupin, N. & Batteux, F. Does inflammatory acne result from imbalance in the keratinocyte innate immune response? Microbes and infection / Institut Pasteur 12, 1085-90 (2010).
  3. Dessinioti, C. & Katsambas, A.D. The Role of Proprionibacterium acnes in acne pathogenesis: facts and controversies. Clinics in Dermatology 28, 2-7 (2010).
  4. Lomholt, H.B. & Kilian, M. Population Genetic Analysis of Propionibacterium acnes Identifies a Subpopulation and Epidemic Clones Associated with Acne. PLoS ONE 5, e12277 (2010).
  5. Hu, J. et al. Comparative Genomics and Transcriptomics of Propionibacterium acnes. PLoS ONE 6, e21581 (2011).
  6. McDowell, A. et al. An expanded multilocus sequence typing scheme for Propionibacterium acnes: investigation of “pathogenic”, “commensal” and antibiotic resistant strains. PloS one 7, e41480 (2012).
  7. Holland, C. et al. Proteomic identification of secreted proteins of Propionibacterium acnes. BMC microbiology 10, 230 (2010).
  8. Nagy, I. et al. Distinct strains of Propionibacterium acnes induce selective human beta-defensin-2 and interleukin-8 expression in human keratinocytes through toll-like receptors. The Journal of investigative dermatology 124, 931-8 (2005).
  9. Burkhart, C.N. & Burkhart, C.G. Microbiology’s principle of biofilms as a major factor in the pathogenesis of acne vulgaris. International Journal of Dermatology 42, 925-927 (2003).
  10. Burkhart, C.G. & Burkhart, C.N. Expanding the microcomedone theory and acne therapeutics: Propionibacterium acnes biofilm produces biological glue that holds corneocytes together to form plug. Journal of the American Academy of Dermatology 57, 722-4 (2007).
  11. Bellew, S., Thiboutot, D. & Del Rosso, J.Q. Pathogenesis of acne vulgaris: what’s new, what’s interesting and what may be clinically relevant. Journal of drugs in dermatology : JDD 10, 582-5 (2011).
  12. Coenye, T., Peeters, E. & Nelis, H.J. Biofilm formation by Propionibacterium acnes is associated with increased resistance to antimicrobial agents and increased production of putative virulence factors. Research in Microbiology 158, 386-392 (2007).

Vaccine industry challenges

Infectious diseases are still the leading global cause of morbidity and mortality. Vaccine-preventable diseases are still responsible for about 25% of the 10 million deaths occurring annually among children under five years of age, and ~25% of adult (15–59 years) deaths are still attributed to infectious diseases.1 Moreover, infectious diseases continue to rise due to an alarming rate of antibiotic resistance among bacteria, and due to the trends of pathogen spreading driven by globalization and enlarged mobility.

Despite the great need to develop novel and more efficient vaccines, the progress has been slow. Current approaches to vaccine antigen discovery are inefficient, costly, and frequently lead to the selection of ineffective targets: only 15% of vaccines that enter clinical trials get market approval.2 It has been estimated that even a 10-percent improvement in predicting failures before embarking on clinical trials could save a pharmaceutical company $100 million in development costs per product.3

Therefore, it is of crucial significance to develop methods, which would predict the efficacy of vaccine candidates in clinical trials with greater certainty.

The reason behind such low success in selecting optimal vaccine candidates lie primarily in the challenges associated with the vaccine antigen selection. Most widely used methods in antigen discovery are:

  • reverse vaccinology,
  • bioinformatics analysis,
  • proteomics, and
  • antigenome technology.

Reverse vaccinology as an approach was validated for the first time on a Gram-negative bacteria, Neisseria meningitidis serogroup B (MenB); although it lead to identification of several antigens (the vaccine has successfully completed Phase III clinical trials), the screening process required large resources and several years to complete.4

Other approaches are similarly laborious and frequently biased. Proteomic analysis of cellular fractions or peptides digested from the bacterial surface has the limitations that not all proteins are equally abundant and prone to digestion, and it is difficult to control enzymatic digestion to preserve the integrity of the cell while maximizing the amount of surface digested proteins. Moreover, the proteomic analysis gives no information about the functional significance and protective potential of the identified antigens.

Antigenome approach relies on the use of sera from the patients who overcame infection or healthy individuals expected to contain protective antibodies. However, this approach too is biased towards antigens that are immunogenic but not necessarily protective, and is not suitable for identifying the antigens containing large conformational epitopes or epitopes created by post-transcriptional modifications (due to the use of a non-native antigen expression system which can display only a limited number of amino acids from a native, pathogen-derived antigen).

Besides the challenges encountered during initial antigen screening and selection, a successful vaccine development is further complicated by the biased experimental methods used during pre-clinical validation of antigen efficacy. For example, relying heavily on the animal models and in vitro testing under artificial laboratory culture conditions are not best practices for evaluating protective potential of the vaccines against strictly human pathogens. Such pathogens are highly adapted to the human tissue environment and have developed multiple mechanisms for evading human immune responses (e.g. binding of components of human complement and fibrinogen, escaping or interfering with phagocytosis, binding human immunoglobulins). These immune evasion mechanisms do not operate in other species and therefore, data obtained from such studies cannot be extrapolated to humans. The current requirement by regulatory authorities for extensive data demonstrating the protective efficacy of vaccine candidates in animal models compounds this problem, whereby those engaged in vaccine development continue to utilize animal models that are not relevant for investigating strictly human pathogens.

For each year of delay in vaccine discovery and development, millions human lives are being lost. Overcoming these challenges should be the highest priority of the scientific community and industry: this is the most powerful motivation behind our research efforts at Origimm.

REFERENCES:

  1. Adamczyk-Poplawska, M., Markowicz, S. & Jagusztyn-Krynicka, E. K. Proteomics for development of vaccine. Journal of proteomics 8, 1–21 (2011).
  2. Kola, I. & Landis, J. Can the pharmaceutical industry reduce attrition rates? Nature reviews. Drug discovery 3, 711-5 (2004).
  3. Innovation or Stagnation. Challenge and Opportunity on the Critical Path to New Medical Products. (Critical white paper). U.S. Department of Health and Human Services. Food and Drug Administration. (2004).
  4. Kaushik, D.K. & Sehgal, D. Developing antibacterial vaccines in genomics and proteomics era. Scandinavian journal of immunology 67, 544-52 (2008).